Vitiligo is an acquired pigmentary disorder of the skin and mucous membranes, and it is characterized by circumscribed depigmented macules and patches. It 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.
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
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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
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.7
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 vitiligo8
Vitiligo is characterized by incomplete penetrance, multiple susceptibility loci, and genetic heterogeneity. The inheritance of vitiligo may involve genes associated with the biosynthesis of melanin, a response to oxidative stress, and regulation of autoimmunity.9
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.
In the United States, the relative rate is 1%.
Vitiligo is relatively common, with a rate of 1-2%. Approximately 30% of cases occur with a familial clustering of cases.
A female preponderance has been reported, but it is not statistically significant and the discrepancy has been attributed to an increase in reporting of cosmetic concerns by female patients.
Vitiligo may appear at any time from birth to senescence, although the onset is most commonly observed in persons aged 10-30 years.
- It rarely is seen in infancy or old age. Nearly all cases of vitiligo are acquired relatively early in life.
- The average age of onset 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 the condition among females.
The most common form of vitiligo is an amelanotic macule or patch surrounded by healthy skin. The macules are chalk or milk-white in color, and lesions are well demarcated.
The lesions are not readily apparent in lightly pigmented individuals; however, they are easily distinguishable with a Wood lamp examination.
Vitiligo manifests as acquired white or hypopigmented macules or patches. The lesions are usually well demarcated, and they are round, oval, or linear in shape. The borders may be convex.6 Lesions enlarge centrifugally over time at an unpredictable rate. Lesions range from millimeters to centimeters in size. Initial lesions occur most frequently on the hands, forearms, feet, and face, favoring a perioral and periocular distribution.
Vitiligo lesions may be localized or generalized, with the latter being more common than the former. Localized vitiligo is restricted to one general area with a segmental or quasidermatomal distribution. Generalized vitiligo implies more than one general area of involvement. In this situation, the macules are usually found on both sides of the trunk, either symmetrically or asymmetrically arrayed.
The most common sites of involvement are the face, neck, and scalp. Many of the most common sites of occurrence are areas subjected to repeated trauma, including the following:
- Bony prominences
- Extensor forearm
- Ventral wrists
- Dorsal hands
- Digital phalanges
Involvement of the mucous membranes is frequently observed in the setting of generalized vitiligo. Vitiligo often occurs around body orifices such as the lips, genitals, gingiva, areolas, and nipples.
Body hair (leukotrichia) in vitiliginous macules may be depigmented. Vitiligo of the scalp usually appears as a localized patch of white or gray hair, but total depigmentation of all scalp hair may occur. Scalp involvement is the most frequent, followed by involvement of the eyebrows, pubic hair, and axillary hair, respectively. Leukotrichia may indicate a poor prognosis in regard to repigmentation. Spontaneous repigmentation of depigmented hair in vitiligo does not occur.
Trichrome vitiligo has an intermediate zone of hypochromia located between the achromic center and the peripheral unaffected skin. The natural evolution of the hypopigmented areas is progression to full depigmentation. This results in 3 shades of color—brown, tan, and white—in the same patient (see Media File 1).
Marginal inflammatory vitiligo results in a red, raised border, which is present from the onset of vitiligo (in rare cases) or which may appear several months or years after the initial onset. A mild pruritus may be present (seeMedia File 2).
Quadrichrome vitiligo is another variant of vitiligo, which reflects the presence of a fourth color (ie, dark brown) at sites of perifollicular repigmentation. A case of pentachrome vitiligo with 5 shades of color has also been described.7
Blue vitiligo results in blue coloration of vitiligo macules. This type has been observed in a patient with postinflammatory hyperpigmentation who then developed vitiligo.
Koebner phenomenon is defined as the development of vitiligo in sites of specific trauma, such as a cut, burn, or abrasion. Minimum injury is required for Koebner phenomenon to occur.
Clinical classifications of vitiligo
The classification system is important because of the special significance assigned by some authorities to each type of vitiligo. The most widely used classification of vitiligo is localized, generalized, and universal types and is based on the distribution, as follows:
- Focal: This type is characterized by one or more macules in one area, most commonly in the distribution of the trigeminal nerve.
- Segmental: This type manifests as one or more macules in a dermatomal or quasidermatomal pattern. It occurs most commonly in children. More than half the patients with segmental vitiligo have patches of white hair or poliosis. This type of vitiligo is not associated with thyroid or other autoimmune disorders.
- Mucosal: Mucous membranes alone are affected.
- Acrofacial: Depigmentation occurs on the distal fingers and periorificial areas.
- Vulgaris: This is characterized by scattered patches that are widely distributed.
- Mixed: Acrofacial and vulgaris vitiligo occur in combination, or segmental and acrofacial vitiligo and/or vulgaris involvement are noted in combination.
- Universal: This is complete or nearly complete depigmentation. It is often associated with multiple endocrinopathy syndrome.
Classification by progression, prognosis, and treatment
When progression, prognosis, and treatment are considered, vitiligo can be classified into 2 major clinical types: segmental and nonsegmental.
- Segmental: This usually has an onset early in life and rapidly spreads in the affected area. The course of segmental vitiligo can arrest, and depigmented patches can persist unchanged for the life of the patient (seeMedia File 3).
- Nonsegmental: This type includes all types of vitiligo, except segmental vitiligo (see Media File 4).10
Theories regarding destruction of melanocytes include autoimmune mechanisms, cytotoxic mechanisms, intrinsic melanocyte defects, oxidant-antioxidant mechanisms, and neural mechanisms.
- Autoimmune and cytotoxic hypotheses: Aberration of immune surveillance results in melanocyte dysfunction or destruction.
- Neural hypothesis: A neurochemical mediator destroys melanocytes or inhibits melanin production.
- Oxidant-antioxidant mechanisms: An intermediate or metabolic product of melanin synthesis causes melanocyte destruction.
- Intrinsic defect of melanocytes: Melanocytes have an inherent abnormality that impedes their growth and differentiation in conditions that support normal melanocytes.
Because none of these theories alone is entirely satisfactory, some have suggested a composite hypothesis
Other Problems to Be Considered
Vitiligo and ocular disease
The uveal tract and retinal pigment epithelium contain pigment cells. Choroidal abnormalities have been reported in up to 30% of patients, and iritis has been reported in approximately 5% of patients. Exophthalmos may occur in the setting of concomitant Graves disease. Uveitis is the most significant ocular abnormality associated with vitiligo. The most severe form of uveitis is seen in the Vogt-Koyanagi-Harada syndrome. This syndrome is characterized by vitiligo, uveitis, aseptic meningitis, dysacusis, tinnitus, poliosis, and alopecia.
Alezzandrini syndrome includes facial vitiligo, poliosis, deafness, and unilateral visual changes. The affected eye has decreased visual acuity and an atrophic iris.6
Although the color of the irides does not change in patients with vitiligo, depigmented areas in pigment epithelium and choroid occur in up to 40% of patients.
Vitiligo and autoimmune disorders
Vitiligo is frequently associated with disorders of autoimmune origin, with thyroid abnormalities being the most common. Vitiligo usually precedes the onset of thyroid dysfunction. Patients with autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy have an increased prevalence of vitiligo. In this genetic syndrome, autoantibodies cause destruction of endocrine cells.11
Moreover, studies suggest that an association exists between a positive family history of vitiligo, autoimmune/endocrine diseases, leukotrichia, and an increased incidence of vitiligo in children. In addition, pediatric patients with a positive family history of vitiligo show an earlier age of disease onset.12
Vitiligo and auditory abnormalities13
Melanin may play a significant role in the establishment and/or maintenance of the structure and function of the auditory system and may modulate the transduction of the auditory stimuli by the inner ear.14 The membranous labyrinth of the inner ear contains melanocytes, and the heaviest pigmentation is present in the scala vestibuli. Because vitiligo affects all melanocytes, auditory disturbances may result. Several studies have described familial vitiligo associated with hearing abnormalities and hypoacusis in 16% of patients younger than 40 years who have vitiligo.14
Vitiligo and melanoma15,16
Vitiligolike depigmentation can occur in patients with malignant melanoma and is believed to result from a T-cell–mediated reaction to antigenic melanoma cells and cross-reactivity to healthy melanocytes. Most patients with melanoma or with vitiligo develop antibodies to similar antigens that are present both on melanocytes and on melanoma cells. These findings support the hypothesis that the clinical link between the 2 diseases results from immune responses to antigens shared by normal and malignant pigment cells. Studies have demonstrated that a halo nevus, hypopigmentation, or depigmentation may occur in patients with melanoma. The depigmentation or hypopigmentation spreads centrifugally from the trunk to other parts of the body. The sites of depigmentation may be remote from the original site of melanoma. Although metastasis has most likely occurred in the majority of patients, active vitiligo in these patients may signal a longer survival time than expected.
Although the diagnosis of vitiligo generally is made on the basis of clinical findings, biopsy is occasionally helpful for differentiating vitiligo from other hypopigmentary disorders.
Vitiligo may be associated with other autoimmune diseases, especially thyroid disease and diabetes mellitus. Other associated autoimmune diseases include pernicious anemia, Addison disease, and alopecia areata. Patients should be made aware of signs and symptoms that suggest the onset of hypothyroidism, diabetes, or other autoimmune disease. If signs or symptoms occur, appropriate tests should be performed.16
- Thyrotropin testing is the most cost-effective screening test for thyroid disease. Antinuclear antibody screening is also helpful. A CBC count with indices helps rule out anemia.
- Clinicians should also consider investigating for serum antithyroglobulin and antithyroid peroxidase antibodies, particularly if thyroid involvement is suspected. Antithyroid peroxidase antibodies are regarded as a sensitive and specific marker of autoimmune thyroid antibodies. Screening for diabetes can be accomplished with fasting blood glucose or glycosylated hemoglobin testing.
Vitiligo is diagnosed by means of inspection with a Wood lamp.
Microscopic examination of involved skin shows a complete absence of melanocytes in association with a total loss of epidermal pigmentation. Superficial perivascular and perifollicular lymphocytic infiltrates may be observed at the margin of vitiliginous lesions, consistent with a cell-mediated process destroying melanocytes. Degenerative changes have been documented in keratinocytes and melanocytes in both the border lesions and adjacent skin. Other documented changes include increased numbers of Langerhans cells, epidermal vacuolization, and thickening of the basement membrane. Loss of pigment and melanocytes in the epidermis is highlighted by Fontana-Masson staining and immunohistochemistry testing.