Vitiligo

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Vitiligo (IPA Template:IPA) or leukoderma is a chronic skin condition that causes loss of pigment, resulting in irregular pale patches of skin. The cause of vitiligo is complex, may be multifactorial, and is not fully understood. There is some evidence suggesting it is caused by a combination of auto-immune, genetic, and environmental factors. Vitiligo is the most common depigmenting disease with a worldwide incidence of 1%.

Human pigmentation diseases, such as vitiligo, have been described for over 3,000 years by different cultures around the world. Some famous texts, as the Eber Papyrus, Atharva Veda or even the Bible, provide a description of “white spotted-diseases” that could include cases of vitiligo. Celsus was the first to use the word “vitiligo” in the first century A.C. and Moriz Kaposi was one of the first to describe the histopathologic features of vitiligo.

Vitiligo can be classified in two clinical subtypes. One is segmented vitiligo, which affects only 1 segment of the body (face, arm or leg); and non-segmented vitiligo, involving more than 1 segment, such as both knees or both hands.

Characteristics of the Subtypes of Vitiligo

	Non-segmental Vitiligo	Segmental Vitiligo
Definition	Involves both sides of the body, most common type	Involves 1 segment of the body (face, arm or leg)
Age	Later onset is more common than in childhood	More common in childhood
Onset and progression	Progressive, with acute episodes	Rapid and stabilizes
Hair involvement	In later stages	Early
Association with other autoimmune conditions	Yes	No
Common location	Areas prone to pressure or friction	Face
Response to autologous grafting	Good response	Relapses
Table adapted from N Engl J Med 2009;360:160-9[1], EDF Vitiligo Guidelines, A. Taieb et al. [2] and J Am Acad Dermatol Mazereeuw-Hautier et al [3]

Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. ^[4][5] The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison’s disease, hyperthyroidism, alopecia areata and pernicious anemia supports this hypothesis,^[6][7][8] but it should also be recognized that the majority of patients with vitiligo do not have any autoimmune disorder.

Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. ^[4][5]

There are numerous conditions that cause hypopigmentation from which vitiligo must be differentiated, and the most common are pityriasis alba, postinflammatory hypopigmentation, tinea versicolor, halo nevus, tuberous sclerosis and albinism.

Vitiligo is the most common human pigmentation disorder, with a prevalence of 1,000/100,000 (1%) of the population. Males and females are equally affected. Half of patients are diagnosed before the age of 20.

Autoimmune diseases and a family history of vitiligo are considered risk factors for developing this condition. A patient that has a relative with vitiligo has an 18 fold increased risk of developing the disease and having an earlier onset of the disease.

The natural history of vitiligo is variable. Depigmentation may be stable or progressive and can cause even a total body depigmentation or remit spontaneously, although spontaneous remission is uncommon.

Vitiligo is an asymptomatic disease that commonly presents during the second decade of life, with a gradual depigmentation over time.^[9][10]

Vitiligo is a chronic skin condition that causes loss of pigment, resulting in irregular pale patches of skin that may be distributed according to different patterns.

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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
• 
  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]
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  Vitiligo. Adapted from Dermatology Atlas^[11]

There are no laboratory abnormalities in vitiligo disease. Consideration should be given to ordering laboratory studies to exclude the presence of other associated conditions such as pernicious anemia, Addison’s disease and thyroid disease.

Although not performed routinely, since the diagnosis of vitiligo is often reached by a thorough history assessment and physical examination, a biopsy of the lesion may show microscopical changes undergoing on the hypopigmented region.

Potent topical corticosteroids (mometasone) and topical calcineurin inhibitors are first-line therapy to achieve repigmentation of vitiligo lesions. Phototherapy has been proven effective for the treatment of generalized vitiligo. Combined treatment with both topical calcineurin inhibitors plus phototherapy have proven more effective in achieving repigmentation in a shorter period of time than single treatments.

Support groups and organizations are available to help individuals learn more about vitiligo, understand treatment options, and find support from other individuals with vitiligo.

• Vitiligo Support International is the largest vitiligo organization in the world. The nonprofit organization provides free access to online message boards, chat rooms, frequently asked questions, information and articles, as well as a patient-referred doctor search. The group advocates on behalf of patients, conducts patient conferences and has local support groups.

• The National Vitiligo Foundation (NVF) is a 501(c)(3) nonprofit organization that provides access to online resources, physician listings, frequently asked questions (etc); funds research through grants and sponsors local support groups and workshop style conferences.

• The American Vitiligo Research Foundation Inc. (AVRF) is a non-profit, tax-exempt charity that aims to increase public awareness about vitiligo and to help those affected by vitiligo, focusing specifically on children and their families. It supports finding a cure through alternatives to animal testing.

• VITFriends, LLC is a support group in the North East USA. Formed in 2004, VITFriends is still growing and touching the world. They are a web-community offering words of encouragement and sharing hope to individuals dealing with Vitiligo. The goal is to raise public awareness about vitiligo.[2]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Guillermo Rodriguez Nava, M.D. [2]

Human pigmentation diseases, such as vitiligo, have been described for over 3,000 years by different cultures around the world. Some famous texts, as the Eber Papyrus, Atharva Veda or even the Bible, provide a description of “white spotted-diseases” that could include cases of vitiligo. Celsus was the first to use the word “vitiligo” in the first century A.C. and Moriz Kaposi was one of the first to describe the histopathologic features of vitiligo.

• Descriptions of human pigmentation diseases have been made for thousands of years.
• The first descriptions of what seems to be vitiligo were written approximately 3000 years ago in the Egyptian text Eber Papyrus^[1] and in the Indian Vedic text Atharva Veda.^[2]
• The Indian text, the Charak Samhita (800 B.C), describes “spreading whiteness” using the Sanskrit word “svitra”.
• The bible mentions a variety of skin diseases, such as leprosy, psoriasis and vitiligo, using one word: “Zara’at“, which means “white spots”.^[3]
• Celsus was the first to use the word “vitiligo” in his book De Medicina (100 A.C.).
• The word “vitiligo” may have been derived from:^[4][5]
  • Vituli: white glistening of the flesh of calves
  • Vitelius: calf
  • VItum: blemish
  • Vitulum: small blemish
• Moriz Kaposi was on of the first to describe the histopathology of vitiligo as a “lack of pigmented granules” in the skin.^[5]
• Damage to periphereal nerves was the first theory that attempted to explain the pathogenesis of vitiligo.^[6]
• The relationship between autoimmune diseases and vitiligo was observed later in history

• In India, they still call vitiligo “sweta kushta” (white leprosy) and women suffering this disease are discriminated against.^[7]
• During the Middle Age in Europe patients with vitiligo were probably diagnosed with leprosy and discriminated against. They were forbidden to work which made them homeless.^[8]
• Other societies, such as Koreans and Germans, were more tolerant with vitiligo patients, as there are portraits of persons who may have had vitiligo. ^[9][10]

• The case of Henry Moss: An African-American, born in Virginia, who at the age of 38 developed vitiligo and started to use his body as an attraction, showing his lesions and charging fees. His case was used as a cornerstone for the debate about the origin of white and black skin. Samuel Stanhope Smith, an American philosopher, said that Henry Moss was the prove that, black skin can turn to white skin. Doctor Benjamin Rush thought that black skin was a form of leprosy and Henry Moss had begun to recover of it. ^[11]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Guillermo Rodriguez Nava, M.D. [2]

Vitiligo is caused by a loss of skin melanocytes. Although the exact mechanism is not known, at least in some cases, an autoimmune process may play a role. ^[1][2] The fact that vitiligo is more prevalent in patients with certain autoimmune disorders, such as Addison’s disease, hyperthyroidism, alopecia areata and pernicious anemia supports this hypothesis,^[3][4][5] but it should also be recognized that the majority of patients with vitiligo do not have any autoimmune disorder.

• Both cellular immunity and humoral immunity have been linked to the pathogenesis of vitiligo.^[6]
  • A predominance of CD8+ T Lymphocytes and Th1 CD4+ T lymphocytes has been found in the perilesional areas^[7][8] exhibiting cytotoxical activity against melanocytes.^[9]
  • Vitiligo patients have circulating IgG and IgA autoantibodies to melanocytes proteins as tyrosinase, TYRP 1 and 2; the melanosomal matrix protein gp100 (Pmel17) and Melan A/MART 1.^[10][11] Passive immunization with monoclonal autoantibodies against the melanocyte membrane protein gp75 (TYRP1) in an animal model induced vitiligo-like lesions.^[12]

• A genetic predisposition to an alteration of the pathway of biopterins and catechols has been observed.
• The high production of toxic metabolites, mainly 6- and 7-BH₄ and noradrenaline, in combination with a redox unbalance lead to melanocyte damage.^[13][14][15]
• Following melanocyte damage, these are eliminated by three possible mechanisms:^[16]
  • Necrosis
  • Apoptosis^[17]
  • Detachment, so-called “melanocytorrhagy“^[18][19]
• Unified theory: the alterations in the membrane of the melanocytes and the liberation of antigens due to apoptosis and necrosis could sensitize the immune cells leading to an autoimmune process.^[20]

Among 656 people with and without vitiligo in 114 families, several mutations (single-nucleotide polymorphisms) were identified in the NALP1 gene.^[21][22] The NALP1 gene, which is on chromosome 17 located at 17p13, is on a cascade that regulates inflammation and cell death, including myeloid and lymphoid cells. NALP1 is expressed at high levels in T cells and Langerhan’s cells, white cells that are involved in skin autoimmunity. Among the inflammatory products of NALP1 are caspase 1 and caspase 5, which activate the inflammatory cytokine interleukin-1β. Interleukin-1β is expressed at high levels in patients with vitiligo.

Of the 656 people, 219 had vitiligo only, 70 had vitiligo with autoimmune thyroid disease, and 60 had vitiligo and other autoimmune diseases. Addison’s disease (typically an autoimmune destruction of the adrenal glands) may be associated with vitiligo as well.

In one of the mutations, the amino acid leucine in the NALP1 protein was replaced by histidine (Leu155->His). The original protein and sequence is highly conserved in evolution, and found in humans, chimpanzee, rhesus monkey, and the bush baby, which means that it’s an important protein and an alteration is likely to be harmful.

The following is the normal DNA and protein sequence in the NALP1 gene:

TCA	CTC	CTC	TAC	CAA
Ser	Leu	Leu	Tyr	Gln
S	L	L	Y	Q

In some cases of vitiligo the first leucine is altered to histidine, by a Leu155→His mutation:

TCA	CAC	CTC	TAC	CAA
Ser	His	Leu	Tyr	Gln
S	H	L	Y	Q

(Leucine is nonpolar and hydrophobic; histidine is positively charged and hydrophilic, so it is unlikely to serve the same function.^{[23] [24]})

The normal sequence of the DNA code for NALP1 of TCACTCCTCTACCAA is replaced in some of these vitiligo families by the sequence TCACACCTCTACCAA,^[25] which respectively code for the amino acid sequence of the normal NALP1 protein SLLYQ being replaced by SHLYQ.^[26]

Histological examination typically shows an absence of melanocytes in the affected areas of the skin. However, it is possible to sometimes identify degenerating melanocytes at the borders of the affected areas. In these patients, normal melanocytes may be found in normal skin areas yet, even in these regions, changes such as abnormal keratinocytes may be found, showing evidence of vacuolated cytoplasm in the basal layers of cells as well as granular extracellular materials.^[27] In certain situations it is possible to identify lymphocytic infiltrates on the margin of the lesions, which is consistent with the underlying immunological mechanism, responsible for the destruction of the melanocytes.^[28]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

There are numerous conditions that cause hypopigmentation from which vitiligo must be differentiated, and the most common are pityriasis alba, postinflammatory hypopigmentation, tinea versicolor, halo nevus, tuberous sclerosis and albinism.

The differential diagnoses of vitiligo include several conditions that should be considered during the diagnosis.^[1][2][3][4]

• Vogt–Koyanagi–Harada syndrome

• Characterized by bilateral uveitis associated with variable auditory, neurological, and cutaneous manifestations due to T cell-mediated destruction of melanin-containing tissues.

• Tuberculoid leprosy

• Manifested as hypochromic patches that are hypoesthetic to light touch

• Tinea versicolor

• May cause vitiligoid changes, generally after treatment in the absence of re-exposure to UV light; the distribution and shape of the lesions and the presence of scaling and green fluorescence of untreated lesions allow a definite diagnosis; may be differentiated by the presence of fine scale, positive potassium hydroxide preparation, and distribution primarily on the trunk and neck;

• Pinta
• Onchocerciasis

• Incontinentia pigmenti achromians (hypomelanosis of Ito)

• Characterized by unilateral or bilateral macular hypopigmented whorls, streaks, and patches corresponding to the Blaschko’s lines that usually develop within the first two years of life; may be associated with other neurological, skeletal, and ocular symptoms.

• Tuberous sclerosis

• Ash-leaf white spots, typically later appearance of other cutaneous symptoms (e.g., shagreen patches, angiofibromas, periungual fibromas, or connective tissue nevi) and possibly neurological sequelae; autosomal dominance.

• Waardenburg’s syndrome

• White forelock, hypertelorism, deafness (varies according to genotype); possible association with congenital megacolon (Hirschsprung’s disease)

• Piebaldism

• White forelock, midline depigmentation of anterior body, bilateral shin depigmentation; autosomal dominance.

• Menkes syndrome

• X-linked recessive condition with diffuse hair and body hypopigmentation, associated with neurodegenerative changes.

A history of trauma or inflammation of the affected area will precede the loss of pigment; occurs in inflammatory disorders accompanied by increased epidermal turnover (e.g., psoriasis, atopic dermatitis), in lichenoid–cytotoxic infiltration of epidermal basal layer (e.g., lichen planus, toxic drug reactions), and in scleroderma; clinically distinguished by identification of the primary skin disease (e.g., scalp or plaque psoriasis, flexural dermatitis for atopic dermatitis, scleroderma plaques), but may coexist with primary disease; in genital areas, lichen sclerosus may resemble vitiligo or be associated with true vitiligo; biopsy is useful in cases that are difficult to diagnose. Other conditions include:

• Discoid lupus erythematosus
• Pityriasis alba

• Common in children with atopy; also may have fine scale, but lesions retain some pigment and are less sharply demarcated.

• Posttraumatic leukoderma

• May occur after deep burns or scarring in which hair follicles are removed entirely or in which the bulge area containing melanocyte precursors is destroyed; can be difficult to distinguish from true vitiligo when scarring is not obvious; may also occur after toxic epidermal necrolysis.

• Topical steroid leukoderma
• Photodistributed vitiligo-like drug reaction in HIV patients
• Vitiligoid depigmentation

• May result from use of systemic drugs (e.g., chloroquine, fluphenazine, physostigmine, imatinib); in rare cases topical imiquimod may also cause vitiligoid depigmentation

• Halo nevus
• Melanoma

• Vitiligoid changes range from halo of depigmentation around a cutaneous melanoma (malignant Sutton’s phenomenon) to more widespread vitiligoid changes; under Wood’s lamp, the margins of such vitiligoid lesions are usually less distinct than in common vitiligo, and depigmentation is usually incomplete

• Mycosis fungoides

• May present with skin depigmentation in dark-skinned patients; clinical diagnosis may be difficult in the absence of signs of inflammation and skin infiltration; biopsy results are diagnostic

• Acquired macular hypomelanosis

• Seen in young adults and frequently referred to as a recalcitrant pityriasis versicolor; white macules are present on the trunk, with more marked involvement on the lower back and axillae; Propionibacterium acnes is a suspected cause of depigmentation

• Annular lichenoid dermatitis of youth
• Idiopathic guttate hypomelanosis

• Presents with hypopigmented macules in a photodistribution on a background of actinic damage primarily on the arms and legs; unlike vitiligo, the macules are usually 5 mm in diameter or less.

• Lichen sclerosus et atrophicus
• Melasma

May be confused with vitiligo when hyperpigmented facial lesions surround normal but hypochromic-looking skin; the pattern of relative hypopigmentation is usually different from that of vitiligo, and examination of other body sites allows a definitive diagnosis

• Sarcoidosis

• Nevus anemicus
• Nevus depigmentosus

• Chemically-induced leukoderma

• Certain chemicals, particularly aromatic derivatives of phenols and catechols, can destroy melanocytes, resulting in chemical leukoderma that may be differentiated from vitiligo by the history of toxin exposure, lesions with bizarre borders and scale, a “confetti-like” distribution, and symptomatic pruritus.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Autoimmune diseases and a family history of vitiligo are considered risk factors for developing this condition. A patient that has a relative with vitiligo has an 18 fold increased risk of developing the disease and having an earlier onset of the disease.

• The prevalence of vitiligo is 1,000/100,000 (1%) of the population.
• The prevalence varies from 100/100,000 (0.1%) up to more than 2,000/100,000 (2%) depending upon the country and age group.^[1]
• A higher prevalence has been observed in India, Romania, Uzbekistan and China.^[2]

• 50% of patients with vitiligo are diagnosed before the age of 20. ^[3]

• While the majority of studies state that both sexes are equally affected,^[4] some studies report a higher incidence of vitiligo in young women.^[5][6]
• Females are diagnosed at a younger age than men.

• There is no difference in the prevalence among races.
• The disease is more often noticed in dark skin patients, and may have a greater psychological impact in dark skin patients.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Alejandro Lemor, M.D. [2]

Autoimmune diseases and a family history of vitiligo are considered risk factors for developing this condition. A patient that has a relative with vitiligo has an 18 fold increased risk of developing the disease and having an earlier onset of the disease.

• The prevalence of vitiligo is 1,000/100,000 (1%) of the population.
• The prevalence varies from 100/100,000 (0.1%) up to more than 2,000/100,000 (2%) depending upon the country and age group.^[1]
• A higher prevalence has been observed in India, Romania, Uzbekistan and China.^[2]

• 50% of patients with vitiligo are diagnosed before the age of 20. ^[3]

• While the majority of studies state that both sexes are equally affected,^[4] some studies report a higher incidence of vitiligo in young women.^[5][6]
• Females are diagnosed at a younger age than men.

• There is no difference in the prevalence among races.
• The disease is more often noticed in dark skin patients, and may have a greater psychological impact in dark skin patients.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Guillermo Rodriguez Nava, M.D. [2]

The natural history of vitiligo is variable. Depigmentation may be stable or progressive and can cause even a total body depigmentation or remit spontaneously, although spontaneous remission is uncommon.

• The natural history of vitiligo is variable.^[1]
• Approximately half of the cases present before the age of 20 years.
• The onset is acute and starts with a rapid loss of pigmentation in sun-exposed and friction areas, most commonly face and extremities.
• A latent period can occur, but remission is uncommon.

• It is difficult to predict the progression and outcome of vitiligo
• Some markers of poor prognosis have been identified:^[2]
  • Family history
  • Mucosal involvement or mucosal vitiligo
  • Koebner phenomenon
  • Nonsegmental vitiligo

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