Background
Vitiligo is an acquired pigmentary disorder of the skin and mucous membranes, and it is characterized by circumscribed depigmented macules and patches. Vitiligo is a progressive disorder in which some or all of the melanocytes in the affected skin are selectively destroyed. Vitiligo affects 0.5-2% of the world population, and the average age of onset is 20 years.
Pathophysiology
Vitiligo is a multifactorial polygenic disorder with a complex pathogenesis. It is related to both genetic and nongenetic factors. Although several theories have been proposed about the pathogenesis of vitiligo, the precise cause remains unknown. Generally agreed upon principles are an absence of functional melanocytes in vitiligo skin and a loss of histochemically recognized melanocytes, owing to their destruction. However, the destruction is most likely a slow process resulting in a progressive decrease of melanocytes. Theories regarding destruction of melanocytes include autoimmune mechanisms,[1] cytotoxic mechanisms, an intrinsic defect of melanocytes, oxidant-antioxidant mechanisms, and neural mechanisms.
Autoimmune destruction of melanocytes
The autoimmune theory proposes alteration in humoral and cellular immunity in the destruction of melanocytes of vitiligo. Thyroid disorders, particularly Hashimoto thyroiditis and Graves disease; other endocrinopathies, such as Addison disease and diabetes mellitus; and alopecia areata; pernicious anemia; inflammatory bowel disease; psoriasis; and autoimmune polyglandular syndrome are all associated with vitiligo.
The most convincing evidence of an autoimmune pathogenesis is the presence of circulating antibodies in patients with vitiligo.[2] The role of humoral immunity is further supported by the observation that melanocytes are destroyed in healthy skin engrafted onto nude mice injected with vitiligo patient sera.[3]
In addition to the involvement of humoral immune mechanisms in the pathogenesis of vitiligo, strong evidence indicates involvement of cellular immunity in vitiligo. Destruction of melanocytes may be directly mediated by autoreactive CD8+ T cells. Activated CD8+ T cells have been demonstrated in perilesional vitiligo skin. In addition, melanocyte-specific T cells have been detected in peripheral blood of patients with autoimmune vitiligo.[4]
Intrinsic defect of melanocytes
Vitiligo melanocytes may have an intrinsic defect leading to melanocyte death. These melanocytes demonstrate various abnormalities, including abnormal, rough endoplasmic reticulum and incompetent synthesis and processing of melanocytes. In addition, homing-receptor dysregulation has also been detected. Early apoptosis of melanocytes has also been suggested as a cause of reduced melanocyte survival; however, subsequent investigation found that the relative apoptosis susceptibility of vitiligo melanocytes was comparable with that of normal control pigment cells.[5]
Disturbance in oxidant-antioxidant system in vitiligo
Oxidant stress may also play an essential role in the pathogenesis of vitiligo. Studies suggest that accumulation of free radicals toxic to melanocytes leads to their destruction. Because patients with vitiligo exhibit a characteristic yellow/green or bluish fluorescence in clinically affected skin, this led to the discovery that the fluorescence is due to accumulation of 2 different oxidized pteridines. The overproduction of pteridines led to the discovery of a metabolic defect in tetrahydrobiopterin homeostasis in patients with vitiligo, which results in the accumulation of melanocytotoxic hydrogen peroxide.[6]
Because oxidative stress has been suggested to be the initial pathogenic event in melanocyte degeneration, several studies have been conducted to evaluate this theory. Recent investigations set out to evaluate the role of oxidative stress by measuring levels of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in lesional and normal skin of patients with vitiligo and in the skin of normal control subjects. They concluded oxidative stress is increased in vitiligo, as indicated by high levels of SOD and low levels of CAT in the skin of vitiligo patients.[7]
Neural theory
Case reports describe patients afflicted with a nerve injury who also have vitiligo have hypopigmentation or depigmentation in denervated areas. Additionally, segmental vitiligo frequently occurs in a dermatomal pattern, which suggests that certain chemical mediators are released from nerve endings that affect melanin production. Further, sweating and vasoconstriction are increased in depigmented patches of vitiligo, implying an increase in adrenergic activity. Finally, increased urinary excretion of homovanillic acid and vanilmandelic acid (neurometabolites) has been documented in patients with vitiligo. This may be a secondary or primary phenomenon.[8]
In summary, although the ultimate cause of vitiligo is not completely known, this condition does not reflect simple melanocyte loss, but possible immunologic alterations and other molecular defects leading to pigment cell destruction; however, melanocytes may be present in depigmented skin after years of onset and may still respond to medical therapy under appropriate stimulation.
Genetics of vitiligo
Vitiligo is characterized by incomplete penetrance, multiple susceptibility loci, and genetic heterogeneity.[9] The inheritance of vitiligo may involve genes associated with the biosynthesis of melanin, a response to oxidative stress, and regulation of autoimmunity.[10]
Human leukocyte antigens (HLAs) may be associated, but not in a consistent manner. For example, HLA-DR4 is increased in blacks, HLA-B13 is increased in Moroccan Jews, and HLA-B35 is increased in Yemenite Jews. An association with HLA-B13 is described in the presence of antithyroid antibodies.
A genome-wide association study of generalized vitiligo in an isolated European founder population identified that the group had significant association with single-nucleotide polymorphisms in a 30-kb LD block on band 6q27, in close vicinity to IDDM8, which is a linkage and an association signal for type I diabetes mellitus and rheumatoid arthritis. Only one gene, SMOC2, is in the region of association, within which SNP rs13208776 attained genome-wide significance for association with other autoimmune diseases and vitiligo.[11]
The age of onset has a genetic component; in another genomewide association study, a quantitative locus for age of onset was found in the major histocompatibility complex class II region near a region associated with generalized vitiligo susceptibility.[12]
Epidemiology
Frequency
United States
In the United States, the relative rate of vitiligo is 1%.
International
Vitiligo is relatively common, with a rate of 1-2%. Approximately 30% of vitiligo cases occur with a familial clustering of cases.
Sex
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.
Age
Vitiligo may appear at any time from birth to senescence, although the onset is most commonly observed in persons aged 10-30 years.
Vitiligo rarely is seen in infancy or old age. Nearly all cases of vitiligo are acquired relatively early in life.
The average age of onset for vitiligo is approximately 20 years. The age of onset is unlikely to vary between the sexes.
Heightened concern about the appearance of the skin may contribute to an early awareness of vitiligo among females.
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