Vitiligo Update Rebat M. Halder, MD, and Johnathan L. Chappell, MD Vitiligo is an acquired dyschromia of the skin in which there is a loss of epidermal melanocytes. The prevalence of vitiligo is approximately 1% in the United States and 0.1-2% worldwide. The exact pathogenesis of vitiligo remains elusive and is likely multi- factorial. After completing this update, participants should be able to discuss the epide- miology of vitiligo and summarize the proposed mechanisms for development of this disease. In addition, they should be able to discuss physical findings, approach to the patient, and some of the therapeutic modalities for this disorder. Semin Cutan Med Surg 28:86-92 © 2009 Elsevier Inc. All rights reserved. itiligo occurs worldwide, with a prevalence of Յ2%. In loci, and genetic heterogeneity. Inheritance may involve Vthe United States, its estimated incidence is 1%. The genes associated with melanin biosynthesis, response to ox- disease usually begins in childhood or young adulthood with idative stress, and regulation of autoimmunity. Because of the a peak onset at 10-30 years. All races are affected, and both frequent association of vitiligo with autoimmune diseases, sexes are equally affected; however, a female preponderance there have been investigations of possible HLA associations has been reported. This discrepancy may potentially be in vitiligo. Several haplotypes have been associated with viti- skewed by increased reporting of cosmetic concerns by fe- ligo in more than one study.1,2 male patients. Vitiligo can be psychologically devastating for The catalase gene has been implicated in the pathogenesis the affected patient. This is especially true in patients with of vitiligo. Most likely a C/T single nucleotide polymorphism darker skin because of the great contrast between the color of in exon 9 of the catalase gene is responsible.3 Reduced cata- vitiliginous skin and surrounding normal skin. Vitiligo can lase enzyme activity has been demonstrated in the epidermis affect quality of life, self-esteem, marriage, and employment, of lesional and nonlesional skin in patients with vitiligo.4 especially in darker-skinned individuals and in certain cul- Catalase is a peroxisomal enzyme found in nearly all organ- tures because of confusion with leprosy and other contagious isms exposed to oxygen that catalyzes the decomposition of skin diseases. Loss of pigment may be viewed by patients as a hydrogen peroxide to water and oxygen. Therein, it serves to threat to racial identity. prevent cell damage by highly reactive oxygen radicals. Etiopathogenesis Role of the Immune System Vitiligo is multifactorial and polygenic. The precise patho- The association of vitiligo with autoimmune conditions is genesis remains elusive; however, several theories have been well established. Thyroid disorders, particularly Hashimoto’s proposed to explain the loss of epidermal melanocytes in this thyroiditis and Graves’ disease, are commonly associated disorder. Proposed mechanisms fall under the rubrics of au- with vitiligo, as are other endocrinopathies, such as Addi- toimmune, biochemical, oxidant-antioxidant, neural, and vi- son’s disease and diabetes mellitus. Alopecia areata, perni- ral. Studies have also pointed to a significant role of genetic cious anemia, systemic lupus erythematosus, inflammatory susceptibility to vitiligo. bowel disease, rheumatoid arthritis, psoriasis, and autoim- mune polyglandular syndrome also are associated, though Genetics of Vitiligo the significance of some of these associations is debated. The Vitiligo is inherited in a non-Mendelian pattern and is char- most compelling argument for an autoimmune pathogenesis acterized by incomplete penetrance, multiple susceptibility is the demonstration of circulating autoantibodies to melano- cytes in the serum of patients with vitiligo. Autoantibodies directed specifically against melanocyte cell surface antigens Department of Dermatology, Howard University College of Medicine, have the ability to kill melanocytes in vivo and in vitro. The Washington, DC. Address reprint requests to Rebat M. Halder, Department of Dermatology, levels of these autoantibodies seem to correlate with disease Howard University College of Medicine, 2041 Georgia Avenue, N.W, extent and activity. One of the autoantigens identified is Washington, DC 20060. E-mail: [email protected]. VIT 40.1 Tyrosinase and TRP-1 and Ϫ2 have been identi- 86 1085-5629/09/$-see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.sder.2009.04.008 Vitiligo update 87 fied as autoantigens as well, but data supporting this claim change and usually no erythema; however, very occasionally, have been conflicting.5 Some patients with vitiligo have inflammation can be seen at the advancing edge of lesions. antibodies to melan A/MART-1, a melanocyte differentia- Lesions are often symmetric and usually enlarge centrifugally tion antigen.6 SOX transcription factors, which are involved in size with time. The increase in size corresponds with a in the differentiation of tissue derived from the neural crest, substantial loss of functioning epidermal and, sometimes, have been identified as melanocytic antigens in vitiligo asso- hair follicle melanocytes. Lesions are typically well demar- ciated with the polyendocrine syndrome.7 Antiorgan anti- cated, but the borders may be scalloped. Lesions are accen- bodies, such as antibodies to thyroglobulin, thyroid micro- tuated with Wood’s lamp examination. Initial lesions occur somes, and gastric parietal cells, also are frequently elevated most frequently on the hands, forearms, feet, and face, al- in patients with vitiligo as compared with healthy control though they may appear anywhere, including the mucous patients.1 Speculation abounds that codon-54 polymor- membranes. Facial vitiligo often favors a periorificial distri- phism in the mannose-binding lectin 2 gene may play a role bution.14 in susceptibility to vitiligo. Mannose-binding lectin is a cal- cium-dependent lectin that causes predisposition to infec- Classification of Vitiligo tions and autoimmune diseases.8 Vitiligo is classified as segmental, acrofacial, generalized, and Oxidant-Antioxidant Role in Vitiligo universal or by pattern of involvement as focal, mixed, and mucosal types. Oxidative stress may also play an important pathogenic role in vitiligo. Several studies suggest that accumulation of free ● Focal vitiligo is usually a solitary macule or a few scat- radicals toxic to melanocytes leads to their destruction. Cul- tered macules in 1 area, most commonly in the distribu- tured melanocytes and the serum of patients with vitiligo tion of the trigeminal nerve, although the neck and often have increased nitric oxide levels, suggesting that nitric trunk are also commonly involved. This form occurs oxide could lead to autodestruction of melanocytes. Com- more commonly in children. pared with control patients, the red cells of vitiligo patients ● Segmental vitiligo presents as unilateral macules in a have lower levels of glutathione, which helps prevent free dermatomal or quasi-dermatomal distribution. This radical mediated injury.9 Thus, vitiligo patients may be sub- type tends to have an early age of onset and, unlike the ject to a greater level of oxidative stress. other types, is not associated with thyroid disease or other autoimmune diseases. Alteration of neural pep- Neural Theory tides has been implicated in the pathogenesis. More Segmental vitiligo often occurs in a dermatomal pattern. This than one half of patients with segmental vitiligo have observation led to a neural hypothesis that proposes certain poliosis. chemical mediators released from nerve endings may cause ● Acrofacial vitiligo presents as depigmentation of the dis- decreased melanin production. Elevated neuropeptide Y lev- tal fingers and periorificial areas. els have been demonstrated in skin affected by vitiligo.10 ● Generalized vitiligo is also termed vitiligo vulgaris. This Decreased sweating occurs in some patches of segmental viti- is the most common pattern. Depigmented patches are ligo, and some patients have been shown to have mild degen- widely and usually symmetrically distributed. erative or regenerative changes in axons and Schwann cells in ● Universal vitiligo presents as depigmented macules and the depigmented areas. patches over most of the body and can be associated with multiple endocrinopathy syndrome (Fig. 1). Viral ● Mucosal vitiligo involves only the mucous membranes Cytomegalovirus (CMV) DNA has been identified in skin (Fig. 2). biopsy specimens of some patients with vitiligo, which raises the question of whether there is viral-induced damage to In patients of darker skin type, there is great contrast between melanocytes in subsets of patients with vitiligo.11 The possi- depigmented and normal skin as shown in Figs. 3 and 4. This is ble involvement of other viruses, such as hepatitis C, HIV, often psychologically devastating. and Epstein-Barr virus has been suggested by some au- thors.12,13 Clinical Variants Trichrome vitiligo is characterized by both depigmented and Convergence Theory hypopigmented macules in addition to normally pigmented Although all the aforementioned hypotheses are attractive, it skin. The natural evolution of the hypopigmented areas is is likely that vitiligo is a result of the convergence of several of progression to full depigmentation. Quadrichrome vitiligo these pathologic pathways. Most experts agree that vitiligo refers to the additional presence of marginal or perifollicular may indeed