Vitiligo: Problems and Solutions

C I hted Ma . VITILIGO Problems and Solutions edited by Torello Lotti University of Florence Florence, Italy Jan...

Author: Torello Lotti | Jana Hercogova

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C

I

hted Ma

.

VITILIGO Problems and Solutions

edited by

Torello Lotti University of Florence Florence, Italy

Jana Hercogova Motol University Hospital, Charles University Prague, Czech Republic

n

MARCEL

MARCEL DEKKER, INC.

DEKKER

Copyrighted Material

NEW YORK' BASEL

Although great care has been taken to provide accurate and current information, neither the author(s) nor the publisher, nor anyone else associated with this publication, shall be liable for any loss, damage, or liability directly or indirectly caused or alleged to be caused by this book. The material contained herein is not intended to provide specific advice or recommendations for any specific situation. Trademark notice: Product or corporate names may be trademarks or registered trademarks and are used only for identification and explanation without intent to infringe.

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Series Introduction

Over the past decade, there has been a vast explosion in new information relating to the art and science of dermatology as well as fundamental cutaneous biology. Furthermore, this information is no longer of interest only to the small but growing specialty of dermatology. Scientists from a wide variety of disciplines have come to recognize both the importance of skin in fundamental biological processes and the broad implications of understanding the pathogenesis of skin disease. As a result, there is now a multidisciplinary and worldwide interest in the progress of dermatology. With these factors in mind, we have undertaken to develop this series of books specifically oriented to dermatology. The scope of the series is purposely broad, with books ranging from pure basic science to practical, applied clinical dermatology. Thus, while there is something for everyone, all volumes in the series will ultimately prove to be valuable additions to the dermatologist's library. The latest addition to the series, edited by Drs. Lotti and Hercogova, is both timely and pertinent. The authors are well known authorities in the field of vitiligo and hypmelanotic syndromes. We trust that this volume will be of broad interest to scientists and clinicians alike. Alan R. Shalita SUNY Health Science Center Brooklyn, New York


iii


Preface

Very few things can be more outrageously and incredibly discriminated against than the color of the skin. When the authors asked themselves what was the inspiration to begin their interest in vitiligo, they had to agree that, at the most irrational level, their scientific interest in vitiligo is probably related to their hate for discrimination. Still now what is probably more challenging in vitiligo is not the chronicity of this progressive depigmenting disorder, but the irrational feeling that these "white spots" may symbolize a punishment sent by God, i.e., a sign of sin. The word "vitiligo" itself could come from the latin word "vitium", a blemish or fault. Irrationally this feeling is apparently affecting the patients' community, the general population, and, at some level even our scientific community. How many physicians will irrationally tell their patients that there is no treatment for vitiligo? The flist part of this book provides a relevant source of updated information from basic science and clinically oriented to eclectically help the practicing dermatologist to make an appropriate therapeutic choice or, if needed, selected multiple therapeutic approaches. On some controversial issues, we provide at least two points of view from different experts in the field always looking for expert guidance for the selection, initiation and follow-up of the different treatments. A special emphasis is given to the self-esteem, body image and self-perception of the vitiligo subjects and to the essential elements for successful counseling. The last chapter in the section is devoted to the most interesting Internet sources, to give the readers a continuously up-to-date source for additional information. The second part of the book is devoted to the other clinically relevant hypomelanotic disorders-sometimes misdiagnosed as vitiligo-and to their possible treatments. Thanks to the efforts of the distinguished international authorship in this book, we tried to clearly identify the different problems facing


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Preface

the researchers and patients dealing with vitiligo and to discuss the many solutions currently available. We hope that all the readers will agree with us that in the end it is not true that there is nothing to do for vitiligo. In fact, just the opposite is true. Torello Lotti, MD Jana Hercogowi, MD


Contents

Series Inlroduction Preface Contributors

iii v xi

1.

Vitiligo: Disease or Symptom? From the Confusion of the Past to Current Doubts Torello Lotti, Giuseppe Hautmann, and lana HercogoviJ

2.

Historical and Psycho-Anthropological Aspects of Vitiligo AIda Morrone

15

3.

Vitiligo: Epidemiology Luigi Naleli

27

4,

Biology of Hypopigmentation Giovanni Menchini. Torello Lalli, El'ridiki Tsoureli-Nikita, lana Hercogova, and lean Paul Ortonne

33

5.

Disorders in Healthy Relatives of Vitiligo Patients Abelel Monem EI Mofty, Medhat A, EI Mofty, and Samia M. Esmat

51

6.

Basic Research: An Update Karin U. Schallreuter

65

7.

Vitiligo: The Autoimmune Hypothesis lean-Claude Bystryn

79

8.

Vitiligo: A Disorder of the Microvessels? Elena Del Bianco, Giuseppe Muscarella, and Torello Lotti

93


vii

Contents

viii

9.

Pathogenesis of Vitiligo: Evidence for a Possible Ongoing Disorder of the Cutaneous Microenvironment Giuseppe Halltmann, Silvia Moretti, Torello Lotti, and Jana HercogovQ

99

10.

Free Radical Damage in the Pathogenesis of Vitiligo JvJauro Picardo and Maria Lucia Dell'Anna

123

II.

Possible Role of Nitric Oxide in the Pathogenesis of Vitiligo Mario Vaccaro and Fabri::io Guarneri

137

12.

Histopathological and Ultrastructural Features of Vitiligo Daniela Massi

145

13.

Clinical Variants of Vitiligo Seung-Kyung Hann and Sungbin [/11

159

14.

Vitiligo in Children Flora B. de Waard-van der Spek and Arnold P. Oranje

173

15.

Vitiligo: Focusing on Clinical Associations with Endocrine, Hematological, Neurological, and Infectious Diseases Alex Llambrich and Jose MO Mascaro

16.

Clinical Associations: Focusing on Autoimmune and Rare Associations G. Primavera and E. Berardesca

179

189

17.

Ocular and Audiological Disorders in Vitiligo Antonella Tosti, Bianca Maria Piraccini, Mati/de [orizzo, and Giovanni Tosti

201

18.

Differential Diagnosis for Vitiligo Wennie Liao and James 1. Nord/und

207

19.

Vitiligo: Emotional Aspects and Personality Giuseppe Hautmann. Torello Lotti, and Jana HercogovQ

225

20.

Therapeutic Guidelines for Vitiligo M. D. Njoo and W. Westerhof

235

21.

Efficacy and Adverse Effects of Psora len Photochemotherapy in Vitiligo Ljubomir Novakovic and John Hawk

253


Contents

22.

ix

Treatment of Vitiligo with UV and Photosensitizing Substances M.L. Flori, M. Pellegrino, A. Molinu, E. Stanghellini, and L. Andreassi

261

23.

Corticosteroids in Vitiligo Alexander 1. Siratigos and Andreas D. Katsambas

271

24.

Vitamins and Vitiligo Evridiki Tsoureli-Nikita, Claudio Comacchi, Giovanni Menchini, and Torello LOlli

281

25.

Alternative Treatments for Vitiligo l/aria Ghersetich, Benedetta Brazzini, Torello Lotti, and Giovanni Menchini

285

26.

Vitiligo: Problems and Surgical Solutions Rafael Falabella

293

27.

Tissue-Engineered Skin in the Treatment of Vitiligo Lesions Andrea Andreassi, Elisa Pianigiani, Paolo Taddeucci, and Michele Fimiani

28.

UV-B Narrowband Microphototherapy: A New Treatment for Vitiligo Giovanni Menchini, Torello LOlli, Evridiki Tsoureli-Nikita, and lana Hercogovit

313

323

29.

Vitiligo: Problems and Nonsurgical Solutions Giovanni Menchini, Torello Lotti, Evridiki Tsoureli-Nikita, and lana Hercogovit

335

30.

Use of UVB in Vitiligo Mario Lecha

341

31.

Cover-Ups: The View of the Cosmetologist Alida DePase

347

32.

Cover-Ups: The View of the Dermatologist Rossana Capezzera, Cristina Zane, and Piergiacomo Calzavara-Pinton

351

33.

Depigmentation and Vitiligo Christina Antoniou and Electra Nicolaidou

359


x

Contents

34.

Vitiligo and the Internet Giovanni Menchini, Torello Lotti, Evridiki Tsoureli-Nikita, and lana Hercogow]

365

35.

Halo Nevus DemelJ'is loannides

369

36.

Alezzandrini's Syndrome Fabrizio Guarneri and Mario Vaccaro

377

37.

Acquired HypomeJanoses R. Konkolova

381

38.

Idiopathic Guttate Hypomelanosis Michelangelo La Placa and Sabina Vaccari

389

39.

Leukonychia Aurora Tedeschi, Maria Rita Nasca, and Giuseppe Micah

393

40.

Vogt-Koyanagi-Harada Syndrome Fabrizio Guarneri, Pasquale Aragona, and Mario Vaccaro

403

41.

Nevus Depigmentosus Beatrice Bianchi, Torello Lotti, and lana Hercogow]

413

42.

Hypomelanosis and Tuberous Sclerosis Complex A. Patrizi and 1. Neri

419

43.

Inherited Hypomelanotic Disorders Nicoletra Cassano and Gino A. Vena

433

44.

Piebaldism Giovanni Maria Palleschi

449

45.

Albinism Evridiki Tsoureli-Nikita, Giovanni Menchini, Torello Lotti, and H. Grossman

461

46.

Chediak-Higashi Syndrome Benedetta Bra;:~ini and l/aria Ghersel ich

473

47.

Melanoma and Vitiligo Dan Forsea

479

48.

Vaccines and Vitiligo Silvia Morelli and Paolo Fabbri

485


Contributors

Arezzo's Hospital and University of Siena, Siena, Italy

Andrea Andreassi L. Andreassi

University of Siena, Siena, Italy

Christina Antoniou University of Athens School of Medicine, "A. Sygros" Hospital, Athens, Greece

University of Messina, Messina, Italy

Pasquale Aragona

E. Berardesca

San Gallicano Dermatological Institute, Rome, Italy

Beatrice Bianchi

University of Florence, Florence, Italy University of Florence, Florence, Italy

Benedetta Brazzini

Piergiacomo Calzavara-Pinton

Spedali Civili, Brescia, Italy

Rossana Capezzera Nicoletta Cassano

Istituto Dermopatico dell'Immacolata, Rome, Italy

Jean-Claude Bystryn New York, U.S.A. Claudio Comacchi

New York University School of Medicine, New York,


Flora B. de Waard-van der Spek Elena Del Bianco


Erasmus Me, Rotterdam, The Netherlands

University of Florence, Florence, Italy


xi

Contributors

xii

Maria Lucia Dell'Anna

San Gallicano Dermatological Institute, Rome,

Italy Bergamo, Italy

Alida DePase

Abdel Monem El Mofty Medhat A. El Mofty

Cairo University, Cairo, Egypt



Samia M. Esmat


Paolo Fabbri

Rafael Falabella

Universidad del Valle, Cali, Colombia

Michele Fimiani


M.l. Flori


Dan Forsea

University of Bucharest, Bucharest, Romania University of Florence, Florence, Italy

Haria Ghersetich

Regional Dermatology Training Center, Moshi, Tanzania

H. Grossman


Fabrizio Guarneri Seung-Kyung Hann Giuseppe Hautmann John Hawk

Korea Institute of Vitiligo Research, Seoul, Korea University of Florence, Florence, Italy

St. John's Institute of Dermatology, London, England

Jana Hercogova

Charles University, University Hospital Motol, Prague,

Czech Republic Sungbin 1m

Korea Institute of Vitiligo Research, Seoul, Korea

Demetris loannides

Aristotle University Medical School, Thessaloniki,

Greece University of Bologna, Bologna, Italy

Matilde lorizzo

University of Athens Medical School, Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece

Andreas D. Katsambas

Charles University, University Hospital Motol, Prague,

R. Konkolova

Czech Republic Michelangelo La Placa Mario Lecha

University of Bologna, Bologna, Italy

University of Barcelona, Barcelona, Spain

Alex Llambrich

Hospital Clinic, Barcelona, Spain


Contributors

xiii

Wennie Liao

University of Cincinnati, Cincinnati, Ohio, U.S.A.

Torello Lotti


Jose M a Mascaro Daniela Massi

Hospital Clinic, Barcelona, Spain


Giovanni Menchini Giuseppe Micali A. MoLinu


CJinica Delmatologica, Universita di Catania, Catania, Italy


Silvia Moretti


Aldo Morrone

Istituto Dermosifilopatico San Gallicano, Rome, Italy University of Florence, Florence, Italy

Giuseppe Muscarella, Luigi Naldi Italy

U.O. Dermatologia, Ospedali Riuniti di Bergamo, Bergamo,

Maria Rita Nasca Italy 1. Neri

Clinica Dermatologica, Universita di Catania, Catania,


Electra Nicolaidou University of Athens School of Medicine, "A. Sygros" Hospital, Athens, Greece M. D. Njoo Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands James J. Nordlund

University of Cincinnati, Cincinnati, Ohio, U.S.A.

Ljubomir Novakovic Arnold P. Oranje

St. John's Institute of Dermatology, London, England

Erasmus MC, Rotterdam, The Netherlands

Jean Paul Ortonne

Hopital L'Archet 2, Nice, France

Giovanni Maria Palleschi A. Patrizi



M. Pellegrino


Elisa Pianigiani


Mauro Picardo


Bianca Maria Piraccini



xiv

G. Primavera

Contributors


Karin U. Schallreuter University of Bradford, Bradford, United Kingdom and Institute for Pigmentary Disorders e. V. in Association with the ErnstMoritz-Arndt University Greifswald Biotechnikum, Greifswald, Germany

E. Stanghellini


Alexander J. Stratigos University of Athens Medical School, Andreas Sygros Hospital for Skin and Venereal Diseases, Athens, Greece Paolo Taddeucci


Aurora Tedeschi

Clinica Dermatologica, Universita di Catania, Catania,

Italy Antonella Tosti Giovanni Tosti

University of Bologna, Bologna, Italy S. Luca Hospital, Trecenta, Italy

Evridiki Tsoureli-Nikita


Sabina Vaccari


Mario Vaccaro


Gino A. Vena

University of Bari, Rome, Italy

W. Westerhof Academic Medical Centre, University of Amsterdam, and Netherlands Institute for Pigment Disorders, Amsterdam, The Netherlands Cristina Zane



1 Vitiligo: Disease or Symptom? From the Confusion of the Past to Current Doubts Torello Lotti and Giuseppe Hautmann University of Florence, Florence, Italy

Jana Hercogova Charles University, Prague, Czech Republic

THE ANCIENT CONFUSION

The word "vitiligo" itselfis said to have been first used by Celsus in the Latin medical classic De re medicina in the first century A.D. With regard to the roots of the term, there seems to be some difference of opinion between lexicographers and dermatologists. Some state that its appearance resembling the white glistening of the flesh of calves (vituli) may have given rise to the generic term vitiligo. Others suggest that it may be derived from vitelius, the Latin word for "calf," because of the white patches in a calf's fur. Some believe that the name represents a blemishing fault that in Latin is called vitium. The origin of the "I" in the word vitiligo is uncertain. It may simply have been introduced for reasons of euphony (1-3). Finally, the Lexicon of the Latin Language published in 1841 in Boston by Facciolati and Forcellini is unable to clarify the terminology. Instead of settling the confusion it even adds to it: "Vitiligo (vitium) a kind of leprosy or cutaneous eruption consisting of spots, sometimes black (?), sometimes white, called morphea, alphus, mel as, leuce; also in general a cutaneous eruption according to Celsus and Pliny (second century A.D.)" (2,4). Thus, it is probable that in ancient times the references to white spots on the skin represented not only vitiligo vulgaris but also other disorders, such as leprosy, that leave white spots on the skin (5). Only in the


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Lotti et al.

last century has the term" vitiligo vulgaris" been used specifically to refer to the acquired, progressive disorder characterized by destruction of melanocytes in the skin and other organs. It seems likely that vitiligo was recognized several millennia before Christian times. Some of the earliest references date from 1500 B.C. (I). Vitiligo has long been confused with leprosy, which may account for the social stigma attached to white spots on the skin (6). The Egyptian Ebers Papyrus (ca. 1500 B.C.) notes several types of leukoderma, one associated with swelling of the skin, the other macular. The first type might be a description of leprosy, the second a description of vitiligo vulgaris. In the early Vedic scripture Alharvaveda (ca. 1500 B.C.) from India, a Kilar or white disease that might represent vitiligo is described. Around 800 B.C., sVitra, meaning "whiteness," is mentioned in the Charaka samhita, a medical treatise. In the ancient Japanese book Amarakosa (1200 B.C.), a collection of Shinto prayers, a disorder called Shira-bilo, meaning "white man," is described. Whether this reference is to albinism, vitiligo, or both is not known. Hippocrates described white spots on the skin but did not seem to distinguish vitiligo and leprosy or other disorders of depigmentation (7). He described many features of vitiligo that have been emphasized in recent years. He noted that the disorder was more easily treated when first diagnosed rather than many years after its onset. In the Bible a variety of disorders characterized by hypo- or depigmentation is described. The Talmud records the association of sudden onset of white hair with vitiligo vulgaris (7). Mercurialis attempted to explain the pathogenesis of the depigmentation in his book, De morbus cUlaneis, suggesting that if phlegm or "mucous blood" rather than blood nourished the skin, the skin turned white. He distinguished the disease from morphea, which he thought was hyperpigmentation. He distinguished several different forms of depigmentation and suggested some therapeutic approaches (8). Near the end of the nineteenth century, when skin diseases were still presented in alphabetical order in many textbooks of dermatology, vitiligo was defined as a pigmentary dystrophy. Gottheil in the late nineteenth century called vitiligo vulgaris a form of atrophy of the pigment cells (9). Louis Brocq termed the lack of pigmentation (achromy) in vitiligous lesions combined with increases in pigmentation (hyperchromy) in the lesions's peripheries "dyschromy" (10). Kaposi was one of the first to describe the histopathological features of vitiligo. He stated that the only anatomical change in vitiligous skin is the lack of pigment granUles in deep rete cells. An increase in pigmentation can be found in the surrounding lesions. Sparsely pigment-laden cells in the corium are unable to add much to the clinical aspect of the skin's pigmentation (II). Obscure etiological mechanisms such as emotional stressors other than traumatic factors triggering the eruption of vitiligo have been extensively discussed by dermatologists. For them, a connection with the nervous system seemed to be evident (10). At the turn of the Copyrighted Material

Vitiligo: Disease or Symptom?

3

twentieth century, different approaches were developed to the treatment of vitiligo. Systemic application of bromides or iodides (or also valerianates) of mercury, antimony, and arsenic did not show much effect. Besnier recommended subcutaneous injection of pilocarpine and saline or bromoiodic baths. Different mixtures containing croton oil, iodine, sublimate, and naphthol ha ve been used topically without convincing therapeutic results (10,12). PRESENT (PARTIAL) KNOWLEDGE: THE DARK SIDES OF THE ACHROMIC DISORDER

Nowadays, vitiligo may be considered and defined as the prototype of the hypomelanotic disorders (3). As is well known, it occurs idiopathically and is acquired in most cases. Clinically, it presents with circumscribed leukoderma that may arise at any age, but it usually appears before the age of 30 years. Approximately 1--4% of the world population is believed to be afflicted. Variable penetrant autosomal dominant inheritance has been suggested, because familial incidence is common. Few or many white macules appear on the exposed areas, such as the dorsal aspects of the hands and the face and neck. Facial lesions are commonly located around the eyes and mouth. Body folds (axilla and groin) may also be initial sites. There are two major commonly recognized forms of vitiligo: generalized and segmental. The generalized form is characterized by depigmented macules involving both sides of the body in a remarkably symmetrical pattern; for each spot on one side of the body, a spot similar in size and location is found on the other side. This type of vitiligo might better be labeled bilateral, symmetrical vitiligo. Segmental vitiligo is characterized by unilateral, symmetrical depigmentation. It could be termed unilateral, asymmetrical vitiligo. This sharply demarcated distinction may raise the question whether symmetrical and asymmetrical vitiligo present the same etiopathological factors or if they represent two different and distinct nosological entities with similar clinical pictures. Confusion may result from the symmetrical segmental forms. One question that must be addressed concerns halo nevi. Halo nevi have been associated with vitiligo and said to represent the same abnormality in a limited form (13,14). Moreover, it has been observed that halo nevi can be observed in almost a third of young patients (7). The question is: Are halo nevi a form of vitiligo? The answer is as yet unknown. VITILIGO BEYOND THE SKIN

Pigmentation of the ears and eyes may also show degenerative changes in some patients with vitiligo. The eyes have two embryologically distinct layers of pigment cells: Immediately behind the neuroretina is the retinal pigment epithelium, which is heavilCBfj}mfjhWRt iYl:lfeYif1?nd layer is the uveal tract,

Lotti et al.

4

consisting of the choroid, the ciliary body, and the iris. Most patients with vitiligo have few symptoms related to the eyes; they might note a slight decrease in night vision or mild photophobia or slight headaches. Discrete areas of depigmentation, with associated pigment hyperplasia involving the choroid and retinal pigment epithelium as well as active uveitis, have been observed in as many as 40% of patients with vitiligo according to Hann and Nordlund (14). Moreover, vitiligo patients exhibit some audiological abnormalities, such as sensorineural hypoacusis, which may be related to involvement of the inner ear melanocytes (14). A few patients have very severe inflammatory eye problems associated with vitiligo. This has been called the Vogt-Koyanagi-Harada or the uveomeningo-encephalic syndrome. This syndrome is characterized by the association of vitiligo, an inflammatory uveitis, and, in some patients, meningeal inflammation and dysacusis. Eye involvement has been described both with bilateral, symmetrical vitiligo and with unilateral, asymmetrical vitiligo (Alezzandrini syndrome). The Vogt-Koyanagi-Harada syndrome has as one manifestation dysacusis; this association suggests that melanocytotoxic processes causing vitiligo can be active in the pigment cells of the stria vascularis of the inner ear. These pigment cells have been demonstrated to be essential for the normal function of the cochlea and provide a pathophysiological basis for loss of hearing in their absence (7). Thus, another very important question is whether vitiligo represents only a cutaneous pigmentary disorder or a systemic disorder of the pigmentary system. Because several patients with vitiligo who have audiological and ophthalmological changes generally do not present symptoms or have vague complaints, involvement of melanocytes in the extracutaneous parts of the body is often overlooked. Thus, the Vogt-Koyanagi-Harada and Alezzandrini syndromes might be considered the most severe manifestations of vitiligo of the skin and the pigmentation of the eyes. Many researchers tend to consider the Vogt-KoyanagiHarada and Alezzandrini syndromes to be different diseases from vitiligo, according to Hann and Nordlund (14). THE SPECIAL DEPIGMENTATION PATTERN OF VITILIGO

Microscopically, vitiligo features the nearly total absence ofmelanocytes and melanin within the epidermis and an increased cellularity in dermal layers (Figs. I and 2). Characteristic histochemical and ultrastructural changes can be observed. The physical disfigurement caused by vitiligous lesions often leads to social embarrassment (6), and it is a major sociopsychological problem in areas where dark skin predominates. The causes of vitiligo are still unknown. Similarly, the precipitating factors are not well delineated. Some factors, such as melanocytotoxic



5

FIGURE 1 Histological picture of vitiligo: a mild diffuse and follicular hyperkeratosis. The papillary dermis shows a minimal fibrotic change. In the basal layer of the epidermis absence of melanocytes is suggested by a lack of cells with perinuclear halo (E-E, x100).

FIGURE 2 Immunohistochemical staining of 8-100 reactivity in vitiligo: presence of dendritic cells in superficial layers of the epidermis (Langerhans cells) and absence of reactivity in the basal layer of epidermis (melanocytes) (x 10).


Lotti et al.

6

chemicals and the Koebner phenomenon (also termed the isomorphic response), are wel1-documented precipitating factors, but their mechanism of action is not completely understood. Depigmentation can be induced by the exposure of some individuals to chemicals that typical1y are derivatives of hydroquinone. It seems that not al1 individuals are equal1y susceptible to the depigmenting effects of wel1-known melanocytotoxic chemicals. Whether this manifestation is vitiligo or depigmentation caused by mechanisms different from those responsible for vitiligo vulgaris is not known. The first chemical to be identified as a melanocytotoxin was monobenzone (15). When workers wore gloves containing this chemical, it destroyed the melanocytes in the skin, leaving the hands of the workers depigmented. This agent has been used for the treatment of individuals with. vitiligo too extensive to repigment (16). There are many other reports of workers in industrial settings exposed to chemicals with structures similar to monobenzone who have developed depigmentation (17-19). There are other reports of individuals developing depigmentation following exposure to commonly encountered items. These include cosmetics (20), possibly paraphenylenediamine hair dyes (21), monobenzone in bleaching creams (22), cinnamic aldehyde in toothpaste (23), and derivatives of hydroquinone in germicides (24). The question is whether such chemical or occupational depigmentation is in fact vitiligo with a known precipitating cause or some other depigmenting disorder. In our opinion, they are different and separate disorders because chemical and occupational depigmentation tend to be limited to the sites of exposure to the melanocytotoxic agent. In addition, the clinical course of depigmentation differs: Vitiligo general1y tends to be progressive throughout the life of affected subjects, whereas chemical depigmentation generally stops spreading after the offending agent is removed. Thus, until there are definitive data to show that the two disorders have a common pathogenetic pathway, we prefer to separate vitiligo from chemical and occupational leukoderma. It is well known that even minor injuries to the skin of patients with vitiligo can leave depigmented areas when healed. This is called the isomorphic response. Small cat scratches, abrasions from fal1ing, surgical wounds, and similar injuries have all been observed to cause depigmentation. Many individuals who develop a sunburn following excessive sun exposure attribute the depigmentation to the burn. These individuals invariably have very fair skin. It is possible that the isomorphic phenomenon activated by the sunburn is responsible for the depigmentation in susceptible individuals. Another explanation is that the individual burned because the skin was depigmented already and did not have the benefit of the protective effects of the pigment system. Gauthier has stressed the importance of the isomor-



7

phic response, suggesting that this phenomenon might explain the onset and distribution of vitiligo (25). Repeated mild trauma associated with rubbing, wearing of clothes, and gentle pressure on the skin was thought to ind uce the depigmentation observed in vitiligo. Nevertheless, this hypothesis must be substantiated. Another question may be represented by gray or white hair: Do they represent a form of vitiligo? Gray hair can be considered the aging of melanocytes of hair follicles, a process associated with interruption of melanogenesis (14). In contrast, white hair usually suggests the complete absence of melanocytes from the papilla of the hair follicle. White hair can be classified into two major types: the first type has a genetic or familial etiology and represents a rather common ca use of partial loss of pigment of the scalp hair in younger adults in the third and fourth decades of life. This type of white hair seems to be different from vitiligo. The second type of complete white hair is uncommon but may be associated with vitiligo. White hair is usually accompanied by interfollicular depigmentation, particularly when it is associated with vitiligo (14). It seems likely that loss ofmelanocytes in the follicles of those wi th vi tiligo represen ts the same destructive process active wi thin the hair bulb follicle.

PATHOGENESIS OF VITILIGO: DISEASE OR SPECTRUM?

The pathogenesis of vitiligo vulgaris is not known, but there are many hypotheses extant, each supported by intriguing data that are outlined in other chapters of this volume. We present them briefly here. Autoimmune Hypothesis

Supporting this hypothesis are the clinical associations of vitiligo with polyglandular failure. This might be the strongest clinical indication available. Patients with lymphoma may develop vitiligo. Most such patients have immune deficiencies that are the cause of freq uent infections that could cause vitiligo (3,7). The same problem is encountered in acquired immunodeficiency syndrome (AIDS) patients who develop vitiligo. It has been hypothesized that such patients might be affected by vitiligo because their immune systems, either humoral or cytotoxic, are impaired (7). The antibodies to melanocytes have been implicated. Nevertheless, although autoantibodies are commonly found in high titers in patients with vitiligo, they are not melanocyte specific. Only about 60% of patients with vitiligo have such antibodies; this might be explained by the presence of low titers to the enzyme. Would such low titers be capable of killing melanocytes?


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It has been suggested that subjects without antibodies might have inactive

disease. Thus, to make any conclusions about the presence of antibodies and disease activity, careful clinical studies are needed. Such antibodies could be the markers of the disease rather than the cause of it. This consideration might explain why melanomas from humans but also many animals share the same antigenic determinants identified by these antibodies (some of which are cytoplasmic and not membrane molecules) (7,26,27). Tyrosinase is usually identified by antibodies. Tyrosinase is thought to be expressed exclusively within the cytoplasm of the melanocyte and not on the cell surface; therefore, the contents of the pigment cells are released into the circulation, where they initiate an immune response. Whether the antigen is an intracellular antigen also requires further investigation. It is still unknown whether the response initiates, accelerates, or merely marks the disease. Thus, these data need confirmation. Antibodies can kill melanocytes in vitro. This suggests that the immune system might be involved in some way in killing melanocytes, at least in some patients with vitiligo. Individuals with endocrine disorders but without vitiligo also had such antibodies; this raises the obvious question of the roie of these antibodies in killing melanocytes. Antibodies can kill melanocytes in vitro and in nude mice bearing human xenografts; this observation has been cited as definitive, but, unfortunately, that is not a valid conclusion. The cytotoxic effects of the antibodies in vitro are complex. The concentration of the antibodies and the antigens involved all remain to be elucidated. Common antigens, such as class I MHC complex, might be involved and make the effect nonspecific. These problems are apparently resolved using nude mice, as the loss ofmelanocytes detectable by DOPA oxidase might represent loss of the enzyme only and not destruction of the melanocytic cell (7). Thus, the role of the antibodies remains to be determined. The plethora of data relating to an autoimmune mechanism for some individuals with vitiligo is very supportive of this hypothesis, but cannot be considered proof of this concept. Genetic/Intrinsic Hypothesis

Vitiligo clusters in families (28,29). This could be the result of environmental melanocytotoxins that affect certain families because of where they live. Moreover, this theory could easily be subsumed in other theories, such as the autocytotoxic or autoimmune theories. The cells have some inherent defect (30,31). This seems inescapable. It is not clear the nature of the insult that makes the melanocyte susceptible to Copyrighted Material


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injury. It is possible that phenols are one environmentally responsible agent. It is also possible that one of the numerous cytokines or chemical mediators of inflammation stimulates the cell and in some way become responsible for cellular death (32). The genetic/intrinsic theory seems to be a vague one that can incorporate almost any abnormalities discovered.

Autocytotoxic Hypothesis Vitiligo seems to affect hyperpigmented skin more often than normal-colored skin (33). This observation does not seem verifiable. The skin around body orifices such as the eyes, mouth, nose, and genitalia is considered hyperpigmented and thus susceptible to vitiligo (33). The skin around orifices like the eyes and mouth is darker in some individuals, but that may be related to vascular abnormalities and not melanin concentrations, especially around the eyes. The genitalia are darker, but vitiligo seems to affect these tissues late in many patients. Thus, these clinical observations appear very tenuous (7). Chemicals with structures similar to melanin intermediates have been added to cultures of melanocytes or melanoma cells, and the cells underwent cytolysis (34,35). That melanin precursors have the potential to be cytotoxic seems real. Compounds such as phenols and quinones in fact are highly reactive. It seems that some of these compounds have a cytotoxicity specific for melanocytes. These in vitro data are intriguing but remain to be confirmed. It is now known that melanin formation begins in the transport vesicles. These observations call for further understanding of how melanin formation occurs, the opportunities for leakage into vital areas of the cell, and the effects of stimulating melanogenesis on such leakage.

Neural Hypothesis The melanocyte and the nervous system are both derived from the neural crest. Both cell types use the amino acid tyrosine for their major end products (melanin and catechols, respectively). Catechols are very similar in structure to some of the intermediates of the melanin pathway. The mostly embyological data seem too weak to draw conclusions. It also has been observed that patients that have sympathectomy can develop a hypopigmented iris, an observation suggesting that the melanocyte is innervated (34). This might be explained as due not to a cytotoxic reaction but rather to a loss of stimulation of uveal melanocytes. Ultrastructural studies demonstrate frequent direct contact between cutaneous nerve endings and melanocytes in vitiligous skin or structural alterations (swelling ofaxons, duplication of the basement membrane, etc.) (37,38); the significance of t~p.fPRJffi~81~t¥jm~h1M1dingsis still unknown.

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Aberrations in f?,-endorphins and met-enkephalin secretion have been reported in vitiligo patients (39). Plasma met-en kephalin levels are generally higher in vitiligo patients (especially in ones with active vitiligo) than in controls. Because it is known that the release of met-en kephalin is affected in humans during stress, it has been suggested that this abnormality may be correlated with the emotional stress suggested to precipitate vitiligo in some patients. Moreover, immunohistochemical observations suggest an increased immunoreactivity to neuropeptide Y and vasoactive intestinal peptide (VIP) at the marginal areas or within vitiligo macules (40). These results are very difficult to interpret, and very little is known about the effects of neuropep tides on human melanocytes. The depigmented skin exhibits abnormalities of the autonomic nervous system (i.e., increased adrenergic tone and decreased parasympathetic tone) (41). This should not be surprising as one of three major epidermal cells is absent, at least functionally. Segmental vitiligo has been one of the strongest clinical manifestations suggesting a neural origin. It also has been suggested that segmental vitiligo responds to therapy with agents that alter neural function (36). The distribution of segmental vitiligo is often said to be dermatomal. In actuality, it is not dermatomal (7) (i.e., it does not follow a specific pattern of cutaneous sensory nerves). It has been stated that without implicating the nervous system it is difficult to explain segmental vitiligo. That might be true, but it is not sufficient for generating an hypothesis. The role of the nervous system in the pathogenesis of vitiligo, if any, is still undefined. Furthermore, no functional association has yet been made between melanocytes and neural cells. Other Hypotheses It has been suggested that melanin synthesis stimulated and altered by melatonin generates radical oxygens, causing melanocyte death (42). The role of melatonin in melanocyte physiology is completely unknown at this time. It has an important role in some animals, including other mammals. It seems to have less effect directly on melanocytes than on the production of melanocytestimulating hormone, at least in other animals. It has not been shown to stimulate free radical formation. It has been suggested that a previously unrecognized biochemical pathway for the production ofthioredoxin is involved in the death ofmelanocytes (43,44). The synthesis of tyrosine in the epidermis and the production of tetrahydrobiopterin have also been implicated (45,46). The latter pathway is interconnected with the thioredoxin pathway. It has been suggested that the depigmentation is a result of a blockade of tyrosine synthesis within keratin-



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ocytes related to an excess accumulation of7-tetrahydrobiopterin within the epidermis and catechols in the serum and tissues (45,46). The accumulation of tetrahydrobiopterin is due to a deficiency in the activity of the enzyme 40'hydroxytetrahydrobiopterin dehydratase that normally recycles the biopterins. The accumulation of 7-tetrahydrobiopterin blocks the production of tyrosine from phenylalanine. It is concluded that the melanocytes are deprived of the essential substrate for synthesis of melanin and that, because of this, the skin turns white. This pathway is intriguing, but the thioredoxin reductase pathway is present in most tissues, and its existence in the skin or melanocytes is still debated. Thus, its role in vitiligo is unknown but would be a good candidate mechanism to support a genetic hypothesis. The role of tetrahydrobiopterin remains to be determined. That melanocytes are present in depigmented skin but incapable of synthesizing melanin due to lack of tyrosine does not correlate well with other data. The histology of the depigmen ted skin suggests an absence of melanocytes. Moreover, this hypothesis does not explain the clinical problem of treating non-hair-bearing skin with PUVA. Such skin usually does not respond well for lack of a reservoir. This hypothesis suggests instead that all skin should respond to therapy in a similar fashion (7). Finally, a variety of animals developing vitiligo manifested progressive depigmentation with loss of active melanocytes such as observed in chickens, mice, cats, dogs, pigs, and horses. Nevertheless, because vitiligo is probably a complex syndrome with multiple etiologies, each animal model may only represent a facet of this complex condition. In fact, each of the several animal models proposed (the Sinclair pig, C57 BL 76 mivi'mivit mouse, Smyth chicken, etc.) helps in the study of different facets of melanocyte destruction; however, until a specific marker of vitiligo is demonstrated, none of them can be considered a specific model for this complex condition CONCLUSIONS: IS VITILIGO A DISEASE OR A SYNDROMIC SPECTRUM? As stated above, the etiology and pathogenesis of vitiligo are not yet known. There are many hypotheses extant, each supported by intriguing data that are currently insufficient to prove the accuracy of the theory. It seems likely that vitiligo vulgaris represents at least one, but more likely several processes that cause melanocyte destruction and inactivation. That this is true is suggested by the various clinical presentations. Besides the typical vitiligo vulgaris, there is segmental vitiligo. It seems unlikely that the same mechanism is responsible for both disorders. Patients with associated polyglandular failure might represent another mechanism. Individual patients present with atypical features. Occasionally a


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patient might have many features of vitiligo vulgaris, such as depigmented patches on the extremities, face, and trunk, but the classic distribution on the fingers, feet, and face is not present. Some individuals show marked loss of pigment from the hair; others show none. These differences might have no importance or significance, or they might be hints that different mechanisms are involved. The various theories outlined above are intended to summarize current popular hypotheses. These theories are not all-inclusive and also are not mutually exclusive (7). It is possible that several mechanisms are operative to produce melanocyte destruction in a given individual, as happens in the Smyth chicken. Thus, we believe that although the clinical picture is quite similar, the etiology and pathogenetic mechanisms vary individual by individual; thus, we propose considering vitiligo as a type of leukoderma involving progressive, acquired depigmentation with unpredictable course. It usually involves integument and probably affects the pigmentary system of other organs. There are other forms of leukoderma, but in our opinion these should be considered distinct entities until more information is available about their pathogenetic mechanisms, and these disorders should be classified as specific forms of depigmentation, such as chemical, occupational depigmentation, or depigmentation associated with melanoma. Finally, we agree with those authors who, on the basis of recent investigation, support the hypothesis that melanocytes are never completely absent in the depigmented epidermis and thus capable of recovering their functionality.

REFERENCES 1.

2. 3. 4. 5. 6. 7.

8.

Nair BKH. Vitiligo. A retrospective. Jnt J Dermatol1978; 17:755-757. Kopera D. Historical aspects and definition of vitiligo. Clin Dermatol 1997; 15841-843. Ortonne JP, Mosher DB, Fitzpatrick DB, eds. Vitiligo and Other Hypomelanoses of Hair and Skin. New York: Plenum, 1983:129-310. Sutton RL. One definition of vitiligo (lett). Arch Dermatol 1965; 91 :288. Singh G, Ansari Z, Dwivedi RN. Vitiligo in ancient Indian medicine (lett). Arch Dermatol 1974; 109:913. Hautmann G, Panconesi E. Vitiligo: a psychologically influenced and influencing disease. Clin Dermatol 1997; 15:879-890. Ortonne JP, Nordlund JJ Vitiligo. In: Nordlund JJ, Boissy RE, Hearing VJ, KlIlg Ra, Ortonne JP, eds. The PIgmentary System. New York: Oxford Press, 1998513-551 Mercurialis H. De Morbis Cutaneis et Omnibus Corporis Humani Excrementis Tractatus. Kansas City, MO: Lowell Press, 1752.


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Gottheil WS. Atrophy of the pigment. In: Gottheil WS, ed. Illustrated Skin Diseases: An Atlas and Textbook. New York: E.B. Treat, 1897:292-304. 10. Brocg L. Traitement des Maladies de la Peau. Paris: Doin, 1892:853-855. II. Kaposi M. Pathologie und Therapie der Hautkrankheiten. 5th ed. Berlin: Urban und Schwarzenberg, 1899:703-707. 12. Neumann 1. Lehrbuch der Hautkrankheiten. Vienna: Braumueller, 1880:438. 13. Lerner AB, Nordlund JJ. Vitiligo. What is it? Is it important? JAMA 1978; 239:1183-1187. 14. Hann SK, Nordlund JJ. Definition of vitiligo. In: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science, 2000:3-6. 15. Oliver EA, Schwartz L, Warren LH. Occupational leukoderma. Arch Dermatol 1940; 16041-44. 16. Mosher DB, Parrish JA, Fitzpatrick TB. Monobenzyl ether of hydroguinone: a retrospective study of treatment of 18 vitiligo patients and a review of the literature. Br J Dermatol 1977; 97:669-679. 17. Bleehen SS. The treatment of hypermelanosis with 4-isopropylcathecol. Br J Dermatol 1976; 94:687-694. 18. O'Malley MA, Mathias T, Priddy M, Molina 0, Grote AA, Halperin WE. Occupational vitiligo due to unsuspected presence of phenolic antioxidant by products in commercial bulk rubber. J Occcup Med 1988; 30:512-516. 19. Tosti A, Gaddoni G, Piraccinl BM, De Maria P. Occupational leukoderma due to phenolic compounds in the ceramic industry? Contact Dermatitis 1991; 25:67-68. 20. Catona A, Lanzer D. Monobenzone, superfade, vitiligo and confetti-like depigmentation. Med J Aust 1987: 146:320-321. 21. Taylor JS, Maibach HI, Fisher AA, Bergfeld WF. Contact leukoderma associated with the use of hair colors. Cutis 1993; 52:273-280. 22. Dogliotti M, Caro 1, Hartdegan RG, Whiting DA. Leucomelanoderma in blacks. A recent epidemic. S Afr J Med 1974; 48: 1555-1558. 23. Mathias CG, Maibach HI, Conant MA. Perioral leukoderma simulating vitiligo from use of a toothpaste containing cinnamic aldehyde. Arch Dermatol 1980; 116:1172-1173 24. Bentley-Phillips R. Occupationalleukodemla following misuse of a disinfectant. S Afr Med J 1974; 48810. 25. Gauthier Y. The importance of Koebner's phenomenon in the induction of vitiligo vulgaris lesions. Eur J Dermatol 1995; 5:704-708. 26. Austin LM, Boissy RE. Mammalian tyrosinase related protein-l is recognized by autoantibodies from vitiligous Smyth chickens. Am J Pat hoi 1995; J 46: 1529-1541. 27. Song YH, Connor E, Li Y, Zorovich B, Balducci P, Maclaren N. The role of tyrosinase in autoimmune vitiligo. Lancet 1994; 344: 1049-1 052. 28. MaJumder PP, Das DK, Li Cc. A genetical model for vitiligo. Am J Hum Genet 1988;43:119-125 29. Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. 30. Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristic ofmelanocytes obtained from adult normal and vitiligo subjects. J Invest Dermatol1987; 88434438


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Puri N, Mojamdar M, Ramaiah A. Growth defects of melanocytes in culture from vitiligo subjects are spontaneously corrected in vivo in repigmenting subjects and can be partially corrected by the addiction of fibroblast-derived growth factors in vitro. Arch Dermatol Res 1989; 281:178-184. Moretti S, Pinzi C, Spallanzani A, et al. Immunohistochemical evidence of cytokine networks during progression of human melanocytic lesions. Int J Cancer 1999; 84: 160-168. Lerner Ab, Nordlund JJ. Vitiligo: loss of pigment in skin, hair and eyes. Jpn J Dermatol1978; 5:1-8. Wick MM. Levodopajdopamine analogs as inhibitors of DNA synthesis in human melanoma cells. J Invest Dermatol ] 989; 92(suppl 5):329s-331 s. Prezioso JA, Fitzgerald GB, Wick MM. Effects of tyrosinase activity on the cytotoxicity of 3,4-dihydroxybenzylamine and buthionine sulfoximine in human melanoma cells. Pigment Cell Res 1990; 3:49-54. Koga M. Vitiligo: a new classification and therapy. Br 1 Dermatol 1977; 97:255261. Morohashi M, Hashimoto K, Guodman F. Ultrastructural studies of vitiligo, Vogt-Koyanagi syndrome and incontinentia pigmenti-achromicans. Arch Dermato] 1977; 113:755-766. Breathnach AS, Bors S, Wyllie LMA. Electronmicroscopy of peripheral nerve terminals and marginal melanocytes in vitiligo. 1 Invest Dermatol 1966; 47: 125140 Mozzanica N, Villa ML, Foppa S, Vignati G, Cattaneo A, Diotti R, Finzi AF. Plasma ex-melanocyte stimulating hormone, l3-endorphin, met-enkephalin, and natural killer activity in vitiligo. J Am Acad Dermatol 1992; 26:693-700. AI'Abadie MSK, Gawkrodger Dl, Senior Hl, Warren MA, Bleehen SS. Neuroultrastructural and neuropeptide studies in vitiligo. Clin Exp Dermatol 1992; 15:284. Al'Abadie MSK, Senior HJ, Bleehen SS, Gawkrodger DJ. Neuropeptide and neural marker studies in vitiligo. Br J Dermatol 1994; 131, 160-165. Slominski A, Paus R, Bomirsi A. Hypothesis: possible role for the melatonin receptor in vitiligo: discussion paper. J R Soc Med 1989; 82:529-541. Schallreuter KU, Wood 1M. Free radical reduction in the human epidermis. Free Radic Bioi Med 1989; 6:519-532. Schallreuter KU, Hordinsky MK, Wood 1M. Thioreduxin reductase: role in free radical reduction in different hypopigmentation disorders. Arch Dermatol 1987; 123:615-619. Schallreuter KU, Wood lN, Pittelkow MR, Gutlich M, Lemke KR, Rodl W, Swanson NN, Hitzemann K, Ziegler L. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263: 1444-1446. Schallreuter KU, Wood lN, Ziegler 1, Lemke KR, Pittelkow MR, Lindsey Nl, Gutlich M. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochem Biophys Acta 1994; 1226: 181-192.

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33. 34. 35.

36. 37.

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39

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41. 42. 43. 44.

45.

46.


2 Historical and Psycho-Anthropological Aspects of Vitiligo Aida Morrone Istituto Dermosifilopatico San Gallicano, Rome, Italy

INTRODUCTION It is extremely difficult to investigate the historical origins of vitiligo due to the fragmentary nature of the available data, the lack of conclusive historical information, and the many philological interpretations of terminology that for centuries contributed to making acceptable historical research difficult. Dealing with the psycho-anthropological aspects is even more difficult, and these are even now the subject of discussion and debate. Several authors have described interesting historical aspects (1~6), but their statements are questionable due to difficulties and errors in interpretation. Research on the historical aspects and definitions of vitiligo remind us that the earliest reports on patchy skin disease appeared circa 1500 B.C. Vitiligo has long been confused with leprosy, which is an important explanation for the social and psychoanthropological stigma attached to white spots on the skin.

ANCIENT REFERENCES

The earliest mention of patchy skin disease that can be interpreted as vitiligo dates back to approximately 1500 B.C. The Ebers Papyrus, dealing with medicine in the age of the Pharoahs, describes two types of skin disease involving changes in the color of the skin. One type, involving tumors and mutations, is likely leprosy, since it is affirmed that "thou shalt not do anything to it" (I).


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The other seems to simply involve a lack of pigmentation; it is likely to be vitiligo, because "only a change in color is found." It is said that in this case a cured was effected (2). References from the same era are found in the ancient sacred books of India, the Alharva Veda from 1400 B.C. (3), in which a disease called Shwelakustha is mentioned, which may be vitiligo. [Shwetakustha is derived from shvet (white) and kushtha (skin disease in general) and according to the Sanskrit dictionary means "making the body repugnant or deteriorating the blood."] Village dwellers used the term charak, meaning something that is hidden or which is spread, both indicating a negative social condition (4,5) In the Alharva Veda, particular reference is made to a disease called kilas. The term "kilas" comes from the Sanskrit word kil, which means "white," in the sense of "casting away." In a 1905 translation of the Alharva Veda, kilas was identified as vitiligo. In the same books, a plant with black seeds is mentioned as being used by [ndians in an attempt to restore normal color to discolored skin: "0 plant, thou produced even color! Render this (spot) its uniform color." Ancient Indian medical literature indicates that the plant generally used was the Bavachee, or Psoralea corylifolia (6). Later it was discovered to contain psoralene, a photodynamically active furocoumarin. In the sacred Buddhist book Vina)' Pitah (624-544 B.C.), the word "kilas" is mentioned in reference to those affected by leukoderma. A collection of Shinto prayers from the Far East, Makatominoharai (1200 B.C.), mentions shira bitu, meaning "white man," which in some cases could be interpretated as vitiligo. Another Indian medical compilation, the Charak Samhita (800 B.C.), mentions a disease called sJlilra, a Sanskrit term meaning "spreading whiteness." L 'Ashwngahida)'a (600 H.C.) attempts to explain the prognostic factors involved in these eruptions (2). In the Greek literature there is great emphasis on "white spots"; for example, the historian Herodotus (484-425 B.C.) reported that foreigners affected by these lesions have probably "sinned against the sun" and should leave the country immediately (7). He wrote in 449 B.C.: If a Persian has leprosy or white sickness he is not allowed to enter into a city or to have dealings with other Persians, he must, they say, have sinned against the sun. Foreigners attacked by this disorder are forced to leave the country, even white pigeons are often driven away as guilty of the same offense. Even Aristotle dealt with whiteness of the skin, which at that time was a disturbing sign, particularly among dark-skinned people (7): Why do boys and women suffer less from white leprosy than men, and old women more than young ones? [s it because leprosy is an escape of


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breath, and bodies of boys are not well ventilated but are thick and those of women are less well ventilated than those of men? For the breath is absorbed in the menses; the smoothness shows the thickness of the flesh. But the flesh of older men and of old women is well aired; for they alone like old buildings have gaps in the construction of their parts. Aristotle also observed that gray hair was a feature of leprosy and reasoned that those who do not get gray hair cannot have leprosy. Although skin disorders with anesthesia and paresthesia were described in seventh-century China, as were various skin disorders in India as far back as 7000 years, and alopecia with sensory changes and skin disturbances in the Berlin Papyrus and the Ebers Papyrus, no evidence of leprosy has been found among ancient Egyptian mummies or in the pre-Columbian Americas (although ceramics of pre-Columbian Middle Andean civilizations display evidence of many other diseases). Leprosy must not have been particularly common, and many leukodermas must have been something other than leprosy. Beyond ancient descriptio!ls, the first clear account of leprosy, according to Kaposi (8), was given by Danielssen and Boeck (9) in 1842. Since it is not possible to find definite evidence for leprosy in texts until the nineteenth century, much historical "leprosy" may, in fact, be vitiligo. The Indian Manu Smirti (200 B.C.) describes sweta kushtha, meaning "white disease"-skin lesions that probably indicated vitiligo (3). It also reports on the lack of respect given people affected by svilra, the loss of skin color. People who had stolen clothing in an earlier life would be reincarnated as people affected by svilra. It appears that skin disorders were reported much earlier in Chinese literature, but descriptions remain rather vague until 600 A.D., when Dohi wrote about Pin-yiial1-hon-lul1, probably today's leprosy (7). In the book Al11arkosha (600 A.D.) the term svitra was used as a synonym for padasphola (flowers on the legs), tlllakpuspi (flowers on the skin), and sidhl71ali (spreading whiteness). In ancient Arabic texts, white skin was expressed using the term baras and others like bahak or bohak (3). The word baras is mentioned in the Koran regarding Jesus (Chap.3, vA8 and Chap.S, v.1 09). The Koran states that' In accord with the will of God, Jesus was able to cure those affected by 'baras'" (10). Patchy skin lesions, likely of leprous nature, were the most important skin diseases mentioned in texts from the early European medical schools up to the end of the fifteenth century. At that time a new important differential diagnosis arose in leukoderma syphiliticum, because the number of lepers decreased and the "new" lues venera, later known as syphilis, began to spread over Europe.


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BIBLICAL REFERENCES

The Bible refers to many different skin conditions using the Hebrew word Zara' at. Some of these were interpreted as signifying sin, representing a punishment sent by God. The biblical term indicates "white spots," but does not necessarily denote vitiligo (7). The roots of the controversy over various interpretations of Zara' at can be found around 25GB.C., when Ptolomy II ordered the translation of the Bible into Greek in order to make it accessible to a grea ter number of people. Referring to persons declared unclean by reason of Zara' at, the scholars of the Septuagint used the term "leprosy," which does not correspond to modern dermatological terminology. At the time, theologians also proposed the term "psoriasis" as a synonym for conditions involving whitening of the skin. The term seems useful as an alternative to the biblical concept of leprosy, as it does not imply the idea of a moral sin and indicates simply any "skin condition." For many years researchers have been interested in the true nature of the biblical "white spots," and many have established that not all references are to leprosy. Rather, they represent a variety of skin conditions and sometimes also mean vitiligo (7). "MODERN" DEFINITIONS

The term vitiligo was used for the first time by A. Cornelius Celsus in his classic text De medicina, which today, after careful examination of its contents and biographical notes, is thought to date from around 25 B.C. (11). Regarding the roots of the term, there seems to be some difference of opinion among experts (12-14). ANCIENT TREATMENTS

In Egypt the use of Ammi majus Linn. for the treatment of vitiligo dates back to the time of Ibn El Bitar in the thirteenth century (15). This plant was mentioned in his book Mofradat Al Adwiya under the name of aatrillal, a Berberian word meaning bird foot. In Egypt it is known as Regl El Ghorab, Gazar El Shy tan, and El Khella El Shytani. It was called Al11mi by Gallen, and in the time of Charles the Great it became Ameum (16). Ibn El Bitar stated that the plant resembled apium, but its flowers were white rather than yellow; its fruit resembled those of celery and khellah (Al11ni visnaga Linn.) but are longer, narrower, and have a pungent and slightly bitter flavor. Ibn El Bitar mentioned that the fruit of this plant was used in the treatment of baras (vitiligo or leukoderma). He also mentioned that the first people to recognize the usefulness of the drug were a Berber tribe in northwest Africa called the Ben Shoeib. This tribe sold the drug to vitiligo sufferers but kept its nature



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secret. El Sherif, quoted by Abou Shady (16), maintained that the drug, mixed with dried "snake skin" and Ruta leaves, powdered and administered in doses of 5 derhum for 5 successive days, would cure bohak, especially if the patient remains in the sun until he sweats. Aatril/a/, a yellowish-brown powder, was sold by a few native Egyptian herbalists as a remedy for vitiligo. It was given in daily doses of 4-12 g, followed by exposure of the affected patches to the sun until blisters formed. Microscopic examination of the commercial powder Aatril/al revealed that it is identical to the powdered seeds of Ammi majus Linn. Fahmy and Abou Shady in 1947 isolated three crystalline compounds from the powder, which were named Al11moidina (8-metoxipsoralene), Aml11idina (8-isoamilinoxipsoralene), and Maiudina or Bergapten (5-metoxipsoralene) (17).

VITILIGO IN THE NINETEENTH CENTURY Toward the end of the nineteenth century, when skin diseases were still presented in alphabetical order in many dermatology textbooks, vitiligo was defined as a pigmentary dystrophy. Louis Brocq (1856-1928) called the lack of pigmentation (achromy) in vitiliginous lesions combined with an increase in pigmentation (hyperchromy) at the periphery of the lesions "dyschromy" ( 18). Moritz Kaposi (1837-1902) was among the first to describe the histopathological features of vitiligo. He stated that the only anatomical change in vitiliginous skin is the lack of pigment granules in deep rete cells. An increase in pigmentation may be found in the surrounding lesions (19). Obscure etiological mechanisms, such as emotional stress or other traumatic factors, may trigger the eruption of vitiligo, and a connection with the nervous system seemed obvious (18,20). At the end of the nineteenth century various approaches were developed in the treatment of vitiligo. Systematic application of bromides or iodides (also valerianates) of mercury, antimony, and arsenic showed no evidence of effectiveness. Ernest Besnier (1831-1909) recommended subcutaneous injections of pilocarpine and saline or bromoiodic baths. Various topical mixtures of croton oil, iodine, sublimate, and naphthol have been used without useful therapeutic results (18,20). Casual use of the terms vitiligo and leukoderma introduced confusion into the scientific literature of the last century and is still felt to this day. Beigel in his 1864 memoir reserved the term vitiligo for those cases in which alteration of the structure and loss of skin pigmentation are observed (21). This obviously is not the way vitiligo is diagnosed today. Pearson et aI., at the beginning of the twentieth century, used the term leukoderma to designate a disease that seemed to be vitiligo (22).


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VITILIGO AND SELF-IMAGE

Vitiligo today often causes social embarrassment (more serious in countries where dark skin is predominant), and the peeled physical appearance of the hypopigmented lesions is often an element in serious psychological disturbances, even among light-skinned people (Fig. 1). Although vitiligo is not a serious illness on a biological level, it becomes one at the psychosomatic level: The anthropological and cultural difficulties implied are such that they create inevitable psychological and sometime psychiatric repercussions (Fig. 2). The skin and the central nervous system, as we know, have a common origin at the ectodermic level, and this common origin justifies the interest in the skin of psychologists, psychiatrists, and neurologists. Even anthropolo-

FIGURE 1 Vitiligo major in an Eritrean patient. MUltiple depigmented macules confluent in large achromic lesions spread to cover almost the entire body.



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FIGURE 2 Vitiligo major in an Ethiopian child. Such depigmentation in dark-skinned individuals can lead to serious identity and cultural problems and to difficulties in their social inclusion.

gists have shown great interest when faced with some skin conditions where cultural and environmental aspects present a peculiar role. The connection between the skin and self-image begins very early in our ontogenesis. In fact, as Anna Freud tells us, at the beginning of life, being hugged, caressed, and blandished make the various parts of the child's body sensitive. It helps the child construct a healthy body image and makes his or her narcissistic libido grow, and it simultaneously promotes the love object by consolidating the bond between mother and child (23). The skin is important in relation to the development of the body-self and the mental-self because of its fundamental tactile function. Among its many other functions, there is a so-called "dermo-optical" function, defined by the psychoanalyst Didier


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Anzieu (24). This function presumes that the skin has some visual function other than being visible. It is to this, the visibility of the skin, that cosmetology is related. Another function of the skin is thought to be that it inscribes "sensorial traces," a sort of pictogram (25). Dermato-cosmetologists are familiar with the painting of faces and bodies in various anthropological-cultural settings, from prehistoric times to now, as if the skin were a mirror that reflects reality (26). The skin constitutes an interface between us and the exterior world and can be considered a sort of envelope that limits and contains our body and conditions our exchanges between interior and exterior. Furthermore, if represents the visible self and the esthetic self. Due to its visibility, the skin may be the site where conflicts regarding exhibitionism are expressed. PSYCHO-ANTHROPOLOGICAL IMPLICATIONS OF VITILIGO

The importance of psychic factors in the etiopathogenesis of vitiligo is by now largely recognized, and the dermatologist, as Panconesi states, should always use a psychosomatic method that takes into account important relations between acute and chronic emotional situations and the appearance or worsening of the skin lesions of vitiligo (27). The skin, because of its bio-physiological complexity, is analogous on an organic level to the structural complexity of the "r" on the psychic plane. Furthermore, it is the multiplicity of its functions that aJ]ows it to express itself as the element of separation and delineation of the "1" and communicate with the exterior world (28). The skin represents at the same time, as the organ that contains the body, an element of separation from and means of communication with the outside world (29). The consequences of vitiligo in the social and working life of the patient are grave, especially in people working in professional fields in which the hands and face represent a tool for interaction with the public. The disease may also lead to manifestations of depression and anxiety that cause difficulties in interpersonal relations (30). Although vitiligo occurs everywhere and can affect all populations, it represents a particularly serious problem for those people whose skin is naturally dark (skin phototypes V and VI) due to the contrast produced by the white patches. Even for patients with lighter skin who tan easily (phototype IV), the disease may be perceived as disfiguring and constitute a true medical tragedy and a simple esthetic problem. For thi reason, although vitiligo is pain-free and not associated with kin flaking, as is psoriasis, it can be a devastating pathology. The contrast between the normal skin color and the white patches can intrude into daily life, marriage, family, friendships, and even the workplace, and the fact that these patients suffer from inferiority



23

complexes, become aggressive, feel shame, and sometimes become isolated and resentful is not surprising (3]). The presence of hypopigmented lesions, particularly in dark-skinned people, may produce psychic tensions and existential difficulties because of the possibility of being mistaken for a person with leprosy. It is interesting to read the personal correspondence of Dr. Marian Levai, an American physician who works in India, reported by Mosher et al. (32): In South India where the old Dravidian language of Tamil is spoken, the condition is known as ven kushtam, "white leprosy." It is often confused with leprosy, which is very prevalent in this area. In brown skin, leprosy starts as hypopigmented mactlles that may, in later stages, become thickened, insensitive to touch and eventually depigmented. Vitiligo, of course, shows only depigmentation but one individual may show both hypopigmented and depigmented macules in different parts of his body at the same time. The confusion of vitiligo with leprosy in the public mind means that it is difficult for young men or women to obtain jobs, especially when involvement of the face or other exposed areas makes the disease so conspicuous.... In India, women can easily retreat into the seclusion of the home; one of my patients did not even want to be seen in the hospital and requested treatment at home. Men, however, are expected to maintain contact with a hostile and suspicious society. In my experience, psychologic tension, nervousness and depression because of vitiligo seem to be more apparent in the educated city dweller. The fact that vitiligo is a long-lasting disease increases the risk of it becoming a major fact in the daily life of patients and families. Lesions on the genitals cause great anguish to those afflicted. In fact, many young patients with vitiligo on the genitals think they must be repugnant to their partners. The involvement of the hair bulbs (hair is chalk white) also carries a heavy weight of embarrassment and preoccupation (31).

CONCLUSION Ginsburg highlights the fact that, when considerating the psychological impact of a skin disease such as vitiligo, is is necessary to remember that the patient's life situation, including the social support network, consisting of family, friends coworkers, and neighbors (but also people known through their professional capacity, such as physicians or teachers) provides emotional warmth and support, as well as practical help, as with child care or financial assistance (33,34). If the patient has a devoted family and friends, he


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or she will probably be able to weather the storm of emotions and practical problems generated by this chronic skin condition much better than if this network is weak or nonexistent. The attitude of intimates, the people closest to the patient, is among the most important factors that determine the impact of any skin disease, including vitiligo (31).

REFERENCES 1. 2. 3. 4.

5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22.

Ebbell B. The Ebers Papyrus. Copenhagen: Levin and Munksgaard, 1937 Nair BKH. Vitiligo-a retrospect. Int J Dermatol 1978; 17:755-757. Koranne RV, Sachdeva KG. Vitiligo. Int J DermatoI 1966; 93:744-753. Whitney WD. Atharva-Veda Samhita (Translation and Notes). Harvard Oriental Series 1905. Vol. 7. Cambridge, MA: Lanman, Harvard University Press, 1905. Singh G, et al. Vitiligo in ancient Indian medicine. Arch Dermatol 1974; 109:913. Fitzpatrick TB, Pathak MA. Historical aspects of methoxsalen and other furocoumarins. J. Invest. Dermatol. 1959; 32:229. Goldman L, Moraites RS, Kitzmiller KW. White spots in biblical times. Arch Dermatol 1966; 93:744-753. Kaposi M. On albinismus and leucoderma. In: Hebra F, Kaposi M, eds. On Diseases of the Skin. Vol. III. London: New Sydenham Society, 1874: 170-177. Goldman, et al. White spots in biblical times. Arch Dermatol 1966; 93:744-753. EI Mofty AM. Vitiligo and Psoralens. New York: Pergamon, 1968. Fitzpatrick TB. Hypomelanosis. South Med J 1964; 57:995-1005. Ortonne JP, Mosher DB, Fitzpatrick DB, eds. Vitiligo and other hypomelanoses of hair and skin. New York: Plenum, 1983:129-310. Nordlund JJ. Vitiligon. In: Thiel'S BH, Dobson RL, eds. Pathogenesis of Skin Disease. New York: Churchill Livingstone, 1986:99. Sutton RL. On definition of vitiligo (lett). Arch Dermatol 1965; 91:288. Ibn El-Bitar. Mofradat Al Adwiya. I. Egyptian Government Press, 1877:4. (In Arabic.) Abou Shady HAA. Ammi majus Linn Thesis for Master of Pharmacy. Fac Med Cairo University, 1948. Fahmy IR. AboLi Shady HAA. Pharmacognostical study and isolation of crystalline constituent, ammoidin. J Pharm Pharmac 1948; 20:281. Brocq L, ed. Traitement des maladies de la peau. Paris: Doin, 1892:853-855. Kaposi M, ed. Pathologie und Therapie del' Hautkrankheiten. 5th ed. Berlin: Urban Lind Schwarzenberg, 1899:624,703-707. Neumann I, ed. Lehrbuch del' Hautkrankheiten. Vienna: Braumi.iller, 1880:438. Beigel H. Beitrag zur Geschichte Lind Pathologie des Albinismus partialis und del' Vitiligo. Nova Acta Akad, K K Leopold Karolin, 1864. Pearson K, et al. A Monograph on Albinism in Man: Drapers' Company Research Memoirs. London: DLilau, 1911.


Historical and Psycho-Anthropological Aspects of Vitiligo 23. 24. 25. 26. 27. 28. 29. 30.

31. 32.

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Panconesi E, Cossidente, Giorgini S, et al. A psychosomatic approch to dermatologic cosmetology. lnt J Dermatol 1983; 22:449-454. Anzieu D. Le Moi-Peau. Paris: Borda, 1985:1-180. Castoriadis-Aulaguier P. La violence de I'interpretation. Paris: P.U.F., 1975:1157. Ovidio.l cosmetici delle donne. A cura di Rosati G. Venice: Marsilio, 1985: 1-78. Panconesi E. Stress and skin diseases: psychosomatic dermatology. Clin Dermato11984; 2:1-272. Obermayer ME. Psychocutaneous Medicine. Springfield, IL: Charles C Thomas, 1955 Pancheri P. Trattato di Medicina Psicosomatica. Vol. I. Firenze: USES Edizioni Scientifiche, 1984:151-179. LePooIIC, Das PK, Van Den Wijngaard R, Bos JD, WesterhofW. Review of the etiopathomechanisll1 of vitiligo: a convergence theory. Exp Dermatol 1993; 2(4)145-153. Hautmann G, Panconesi E. Vitiligo: a psychologically influenced and Influencing Disease. Clin Dermatol 1997; 15:879-890 Mosher D, Fitzpatrick T, Ortonne J, Hori Y. Hypomelanoses and hypermelanoses. In: Freedberg I, et aI., eds. Fitzpatrick's Dermatology in General Medicine. New York: McGraw-Hill, 1999:949. Ginsburg TH. The psychological impact of skin disease: an overview. Dermatol C1in 1966; 14:473-484. Greenblatt M, Becerna RM, Sorafetinides EA. Social networks and mental health: an overview. Am J Psychiatry 1982; 139:977-983.



3 Vitiligo: Epidemiology Luigi Naldi U.O. Dermatologia, Ospedali Riuniti di Bergamo, Bergamo, Italy

The main objective of epidemiology is to find a means to prevent disease onset (primary prevention) and to restore health once a disease has developed (secondary prevention). Others are to evaluate and optimize health care. There are limited data on vitiligo to help address these objectives. DESCRIPTIVE EPIDEMIOLOGY

The usual measures used to describe the distribution of a disease in a given population are incidence and prevalence. Incidence refers to those cases newly developed in a population over a given time period. Prevalence refers to those cases that are present in a given population, irrespective of their onset, at a point in time (point prevalence) or over a longer period of time (period prevalence). Prevalence depends on incidence and on the average duration of the disease in the population. If a disease persists without a cure for a long time, it may give rise to significant prevalence rates even if its incidence rates are remarkably low. It should be noted that incidence estimates require an onset for the disease to be precisely defined. For many chronic disorders characterized by subtle prodromal signs and symptoms like vitiligo, such an onset may be difficult to establish. Data on the prevalence of vitiligo in the general population are limited. Point prevalence estimates have been obtained by the First Health and Nutrition Examination Survey (HANES I study) organized by the National Institutes of Health during the period 1971-1974 in the United States and Copyrighted Material

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recruiting a representative sample of7514 people aged 1-74 years (1). Vitiligo prevalence was estimated at 4.9 cases per 1000 people (3.8 cases per 1000 males, 6.2 cases per 1000 females). In the study, the prevalence of vitiligo increased from 0.6 case per 1000 at age 1-5 years to 13.6 cases per 1000 after age 65. A point prevalence estimate of 3.8 cases per 1000 was obtained in a study conducted on the Bornholm Island in Denmark (2). These estimates are lower than the I % commonly reported. To the best of this author's knowledge, no estimates of incidence rates are available. Based on the prevalence rates mentioned above and considering that the disease tends to persist over time, it seems reasonable to foresee incidence rates in the order of a few new cases per 100,000 people per year. The median age at onset as estimated in a sample of patient members of the U.K. Vitiligo Society, was about 13 years (3). In a study of 160 families with at least one member suffering from vitiligo, the mean age at onset was estimated at about 19 years among males and 24 years among females (4). Vitiligo is an important cause of disability, especially in young people. In spite of not being one of the ten most frequently reported skin disorders in the HANES I study, vitiligo ranked fifth in the study among the diseases that were more frequently reported as a reason for concern in the age group 25-34 years. ANALYTICAL EPIDEMIOLOGY The main purpose of analytical studies, including case-control and cohort studies, is to identify factors that may influence the onset of a disease. Their results are expressed in terms of relative risks or odds ratios. The relative risk is the ratio of disease incidence among those exposed to a purported causal factor (risk factor) to the incidence among the unexposed. When derived from case-control studies, odds ratios provide an estimate of the relative risk. Causation of vitiligo is a complex phenomenon, involving both genetic and environmental factors. There are largely divergent estimates of the proportion of individuals with vitiligo reporting a family history of the disease. Reasons for such variations may include heterogeneous criteria to define cases and different modalities to collect a family history of the disease. It should be noted, for example, that it is quite plausible that a history of vitiligo in one family member may influence the request of consultation for another family member (ascertainment bias). Unfortunately, there are no data concerning vitiligo patients sampled from the general population. In most studies, about 20% of people with vitiligo report a first-degree relative as suffering from vitiligo. In a family study, children of the proband had a 1.7-fold increased risk of developing vitiligo as compared with other family members (4). In the same study, the risk of vitiligo as compared with the general population was, respectively, 7-fold higher among the parents of the proband, 12-fold higher


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among brothers and sisters, and 36-fold higher among the proband's children. The family aggregation of vitiligo does not indicate simple mendel ian transmission. It has been proposed that several recessive alleles at different autosomal loci should interact in an epistatic way to develop vitiligo. A number of studies on the association of vitiligo with major histocompatibility antigens (HLA) have been conducted, but they are inconclusive, suggesting, at most, the existence of heterogeneous associations in different ethnic groups: a positive association with HLA-DR4 and a negative one with DR3 in blacks, a positive association with BW-35 among Yemenite Jews, a positive association with DR6 in the Dutch population, and a positive association with the rare DRW 12 antigen in the German population. We are not aware of any formal analytical study assessing the potential role of environmental factors in the development of vitiligo. Interestingly, vitiligo has been associated with a number of pathological conditions which, in many instances, are immune-related diseases (Table I). It should be noted that, even if no confirmatory epidemiological data are available, the disease onset is frequently associated with stressful life events. Finally, it is common clinical experience to observe the development of new vitiligo lesions in the skin site of a physical trauma (Koebner phenomenon).

CLINICAL EPIDEMIOLOGY: NATURAL HISTORY AND PROGNOSIS There are limited data concerning the natural history and prognosis of vitiligo. A prognostic study should be based on a representative sample of affected individuals followed for a sufficiently long period of time, loss to follow-up should be reduced to a minimum, outcome measures should be clearly defined at the beginning of the study, and adequate analytical methods should employed (survival analysis, Cox models).

TABLE 1

Pathological Conditions Associated with Vitiligo

Alopecia areata Pernicious anemia IgA selective defect Thyroid diseases (frequently associated with autoantibodies) Addison's disease Congenital melanocytic nevi MELAS syndrome (mitochondrial encephalomyopathy, lactic acidosis, and stroke episodes syndrome)


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Segmental vitiligo, which in many series accounts for 10-20% of the affected individuals, have an earlier onset and a more rapid evolution as compared with generalized vitiligo (5). Moreover, segmental vitiligo is rarely associated with immune-related disorders, the Koebner phenomenon, or stressful life events. Once it appears, vitiligo follows a chronic course. In segmental vitiligo, disease activity seems usually to cease with the extension of the disease to the involved dermatome within one year, while new lesions can appear lifelong in generalized vitiligo. In a cohort study involving 61 patients, the Koebner phenomenon, experimentally induced, had a prognostic value correlated with disease activity (6). According to a survey conducted on a large sample of patients members of the U.K. Vitiligo Society, only about 14% of patients experienced a spontaneous improvement of their disease at some point during their life. Patients with a more limited extension of the disease more frequently reported spontaneous improvement compared to patients with more extensive disease (3). Vitiligo has a remarkable impact on the patient's quality of life, wellbeing, and social life (7). It has been documented that an intervention providing psychological support according to a cognitive-behavioral paradigm may have an impact on the disease burden and severity (8). Few data are available concerning factors that may influence therapeutic choices and preferences of patients and physicians. In the already mentioned survey involving members of the U.K. Vitiligo Society, about 40% of male patients and 70% of females reported a regular use of camouflage, while only about 20% of all patients had undertaken a medical or surgical procedures at the same stage of their disease. A survey of 332 Dutch dermatologists documented that only 16% of all dermatologists regularly offered their vitiligo patients an active treatment (9). There was no consensus on the active treatment of choice. Such a situation may be common to other countries. In Holland it has been documented that the development and dissemination of clinical guidelines based on the results of three systematic reviews resulted in better agreement between dermatologists on treatment strategies. These systematic reviews indicated that topical high-potency steroids and narrow-band ultraviolet B light irradiation were the treatment modalities supported by the best available evidence for, respectively, localized vitiligo and generalized vitiligo (10). SUMMARY

Vitiligo is a relatively common skin disease affecting 3-5 individuals per 1000 people. The causative model probably involves genetic-environmental interaction, but the environmental factors are largely unknown. Epidemiological research may contribute to a better understanding of the etiological and


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prognostic factors and aid in the evaluation of the long-term outcome of the disease, improving its management.

REFERENCES I.

2. 3. 4. 5. 6.

7. 8.

9.

10.

Johnson M-LT, Roberts J. Skin conditions and related need for medical care among person 1-74 years. U.S. Department of Health, Education and Welfare Publication No. (PHS) 79-1660, Hyattsville, MD, 1978. Howitz J, Brodthagen H, Schwartz M, et al. Prevalence of vitiligo. Arch Dermatol 1977; 113:47-52. Agarwal G. Vitiligo: an under-estimated problem. Fam Pract 1998; 15:S19S23 Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Br J Dermatol 1988; 118:223-228. Njoo MD, Das PK, Bos JD, Westerhof W. Association of the Koebner phenomenon with disease activity and therapeutic responsiveness in vitiligo vulgaris. Arch Dermatol 1999; 135:407-413. Kent G, Al'Abadie M. Psychologic effects of vitiligo: a critical incident analysis. J Am Acad Dermatol 1996; 35:895-898. Papadopoulos L, Bor R, Legg C. Coping with disfiguring effects of vitiligo: a preliminary investigation into the effects of cognitive-behavioural therapy. Br J Med Psychol 1999; 72:383-896. Njoo MD, Bossuyt PM, Westerhof W. Management of vitiligo. Results of a questionnaire among dermatologists in the Netherlands. lnt J Dermatol 1999; 38:866-872 Njoo MD, Westerhof W, Bos JD, Bossuyt PM. The development of guidelines for the treatment of vitiligo. Arch Dermatol 1999; 135:1514-1521.



4 Biology of Hypopigmentation Giovanni Menchini and Torello Lotti University of Florence, Florence, Italy

Evridiki Tsoureli-Nikita University of Siena, Siena, Italy

Jana Hercogova Charles University, Prague, Czech Republic

Jean Paul Ortonne Hopital L'Archet 2, Nice, France

The substance responsible for skin color is melanin, a pigment produced by melanocytes and transferred to surrounding keratinocytes. Absence or loss of pigmentation of the skin is due to three main etiological factors: an absence/ loss of melanocytes, a deficit of melanin formation, or no melanocytic etiology (Table I). The most frequent diseases characterized by white patches are shown in Table 2, along with the related etio-pathogenesis of hypopigmentation. CONGENITAL ALTERATION OF PIGMENTATION

The diseases characterized by congenital alteration of pigmentation are normally due to a genetic defect that alters the melanin synthesis/distribution or that regulates the multistep process of commitment of neural crest cells to a differentiated cell type (primarily the melanocyte) or melanosome biology (transport, transfer, biogenesis, melanization) (Tables 3-6) (44). Of the congenital alterations in pigmentation, only nevus anemicus is not characterized Copyrighted Material

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Co)

.l:-

TABLE

1

Etiological Factors of Hypopigmentary Disorders

Etiological factors ()

Chemical

0

reactivity always fell below 10% of the epidermis, they were classified as nonreactive. The lesional skin reactivity for GM-CSF, SCF, and bFGF fell into the 11-30% category, and the reaction for IL-6 and TNF-O' into the 31-50% category. On the contrary, in

(a)

(b) FIGURE 5 Immunohistochemical staining of C-Kit reactivity in lesional (a) and perilesional (b) skin (x 10): absence of c-Kit expression in lesional skin and presence of this receptor in perilesional skin on several basal dendritic cells.


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perilesional skin and nonlesional skin, the percentages of stained epidermis for GM-CSF and bFGF were higher (51~100% and 3150%, respectively) and for IL-6 and TNF-Cl' lower (11-30% for both) (117). The findings for SCF were the same for perilesional and nonlesional skin (3l~50%). The expression of the epidermal receptors indicated no significant difference in GM-CSF and IL-6 receptors in lesional and perilesional skin, whereas the expression of c-KIT was significantly higher in perilesional skin than in lesional one. Figures 1-5 show the immunohistochemical reactivity of IL-6, GM-CSF, bFGF, SCF, and c-Kit in lesional and perilesional skin. CONCLUSIONS

The etiology and pathogenesis of vitiligo are not clearly understood. Various causative factors have been implicated in the depigmentation processes of vitiligo, including cytological, environmental, immunological, and neurological destruction of melanocytes. Many pathogenetic hypotheses, each supported by intriguing data, have been proposed. The various theories outlined above are intended to summarize current popular hypotheses. These theories are not all-inclusive, and they are not mutually exclusive. It is possible that several mechanisms are operative in producing melanocyte destruction in a given individual. The recent data here discussed (117) seem to provide evidence of an important change in the expression of epidermal cytokines in vitiligous skin. This modifica tion, which supports the eclectic theory, does not seem to contradict the other hypotheses. REFERENCES I.

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Ortonne JP, Bose SK. Vitiligo: where do we stand? Pigment Cell Res 1993; 6:61-72. Ortonne JP, Mosher DB, Fitzpatrick TB, eds. Histopatology of Vitiligo and Other Hypomelanoses of Hair and Skin. New York: Plenum Medical, 1993: 129-310 Birbeck M, Breathnach A, Everall J. An electron microscope study of basal melanocytes and high level clear cells (Langerhans cells) in vitiligo. J Invest Dermatol1961; 37:51-64. Le Poole IC, van den Wijngaard RM, Westerhof W, et al. Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993; 100:816-822. Schallreuter KU, Lemke R, Brandt 0, et al. Vitiligo and other diseases: coexistence or true association? Dermatology 1994; 188:269-275.

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D'Amelio R, Frati C, Fattorossi A. Peripheral T-cell ubset imbalance in patients with vitiligo and in their apparently healthy first-degree relatives. Ann Allergy 1990; 65143-145. Masala C, Frati C, Amendolea MA. Gastric parietal cell antibodies and chronic gastritis in subjects with vitiligo and in their apparently healthy first-degree relatives. lmmunol Clin Sper 1982; I: 1-8. Kumari J. Vitiligo treated with topical clobetasol propionate. Arch DermatoJ 1984; 120:631-633 Kandil E. Treatmant of vitiligo with 0.1 % bethamethazone 17-valerate-a double blind trial. Br J Dermatol 1974; 91 :457-460. Norris DA, Kissinger RM, Naughton GM. Evidence for immunologic mechanisms in human vitiligo: patients' sera induce damage to human melanocytes in vitro by complement mediated damage and antibody-dependent cellular toxicity. J Invest Dermatol 1988; 90:783-789. Harning R, Cui J, Bystryn Jc. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 1991; 97: 1078-1 080. Betterle C, Caretto A, De Zio A, et al. Incidence and significance of organspecific autoimmune disorders (clinical, latent or only autoantibodies) in patients with vitiligo. Dermatologica 1985; 171:419-423. Naughton GK, Eisinger M, Bystryn Jc. Antibodies to normal melanocytes in vitiligo. J Exp Med 1983; 158:246-251 Bystryn JC, Naughton GK. The significance of vitiligo antibodies. J Dermatol 1985; 12:1-9 Xia P, Geoghegan WD, Jordan RE. Vitiligo antibodies: studies of subclass distribution and complement activation. J Dermatol 1991; 96:627. Aronson PJ, Hashimoto K. Association of IgA antimelanoma antibodies in the sera of vitiligo patients with active disease. J Jnvest Dermatol 1987; 88: 475. Aronson Pl, Hashimoto K. Timed immunoperoxidase gray scale cytologic analysis correlates elevated IgA antimelanoma antibodies in vitiligo patients sera with depigmentation. J Invest Dermatol 1989; 92:397. Naughton G K, Reggiardo MD, Bystryn Jc. Correlation between vitiligo antibodies and extent of depigmentation in vitiligo. J Am Acad Dermatol 1986; J5:978-98 J. Norris DA, Capin L, Muglia 11. Enhanced susceptibility of melanocytes to different immunologic effector mechanisms in vitro: potential mechanisms for postinflammatory hypopigmentation and vitiligo. Pigment Cell Res 1988; 1: 113-119 Cui J, Arita Y, Bystryn Jc. Characterization of vitiligo antigens. Pigment Cell Res 1995; 8:53-60 Song YH, Connor E, Li Y. The role of tyrosine in autoimmune vitiligo. Lancet 1994; 344: 1049-1052. Cui l, Harning R, Henn M. Identification of pigment cell antigen defined by vitiligo antibodies. J Invest Dermatol 1992; 98: 162-165.


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Bystryn IC, Cui I, Hariya Y. Melanoma and vitiligo are associated with antibody responses to similar pigment cell antigen. 1 Invest Dermatol 1992; 4:629 Cui 1, Bystryn Ie. Melanoma and vitiligo are associated with antibody responses to similar antigens on pigment cells. Arch Dermatol 1995; 131:314318 Gilhar A, Pillar T, David M. Melanocytes and Langerhans cells in aged versus young skin before and after transplantation into nude mice. 1 Invest Dermatol 1991; 96:2JO-214. Gilhar A, Zelickson B, Ulman Y. In vivo destruction of melanocytes by the IgG fraction of serum from patients of vitiligo. 1 Invest Dermatol 1995; 105:683-686. Hann SK, Park YK, Lee KG, et a!. Epidermal changes in active vitiligo. ] Dermatol 1992; 19:217-222. Le-Poole IC, van den Wijngaard RM, Westerhof W. Presence of T cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am I Patho! 1996; 148:1219-1228 Al Bradi AM, Foulis AK, Todd PM. Abnormal expression of MHC class II and ICAM-I by melanocytes in vitiligo. I Pathol 1993; 169:203-206 Ahn SK, Choi EH, Lee SH Immunohistochemical studies from vitiligo. Yonsei Med 1 1994; 35:404-410. Visseren MA, Van Elsas E, Van der Voort M. CTL specific for the tyrosinase can be induced from healthy blood to lyse melanoma cells. 1 Immunol 1995; 134:3991-3998. Ogg GS, Rod DP, Romero P. High frequency of skin-homing melanocytespecific cytotoxic T lymphocytes in autoimmune vitiligo. 1 Exp Med 1998; 188:1203-1208. Boissy RE, Fite KV, Smith 1R 11'. Progressive cytolytic changes during the development of delayed feather amelanosis and associated choroidal defects in DAM chicken line-a vitiligo model. Am I Pathol. 1983; Ill: 197-212. Boissy RE, Lamont S1, Smith IR II'. Persistence of abnormal melanocytes in immunosuppressed chickens of the immune DAM line. Cell Tissue Res 1984; 235663-668. Nath SK, Majumder PP, Nordlund 11. Genetic epidemiology of vitiligo: multi locus recessivity crossvalidated. Am 1 Hum Genet 1994; 55:981-990. Ramaiah A, Mojamdar M, Amarnath VM. Vitiligo in the SSK community of Bangalore. Indian I Dermatol 1988; 54:251-254. Majumder PP, Nordlund JJ, Nath SK. Pattern of familial aggregation of vitiligo. Arch Dermatol 1993; 129:994-998. Puri N, Mojamdar M, Ramaiah A. In vitro growth characteristics of melanocytes obtained from adult normal and vitiligo subjects. I Invest Dermatol 1987; 88:434-438. Boissy RE, Beato KE, Nordlund II. Dilated rough endoplasmic reticulum and premature cell death in melanocytes cultured from the vitiligo mouse. Am I Pathol 1991; l38:1511-1525.

24.

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29. 30. 31.

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35. 36. 37. 38.

39.


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40. 41.

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Bowers RR, Harmon J, Prescott S. Fowl model for vitiligo: genetic regulation on the fate of the melanocytes. Pigment Cell Res 1992; 2:242-248. Cerundolo R, De Caprariis D, Esposito L. Vitiligo in two water buffaloes. Histological, histochemical and ultrastructural investigations. Pigment Cell Res 1993; 6:23-28. Norris A, Todd C, Graham A, et al. The expression of the c-kit receptor by epidermal melanocytes may be reduced in vitiligo. Br J Dermatol 1996; 134: 299-306. Gellin GA, M'aibach HI, Misiaszek MH. Detection of environmental depigmenting substances. Contact Dermatitis 1979; 5:201-213. O'Malley MA, Mathias T, Priddy M. Occupational vitiligo due to unsuspected presence of phenolic antioxidant by products in commercial bulk rubber. J Occup Med 1988; 30:512-516. Lerner AB. On the etiology of vitiligo and gray hair. Am J Med 1971; 51:141147. Kovacs SO. Vitiligo. J Am Acad Dermatol 1998; 38:647-666. Riley PA. Mechanism of pigment cell toxicity produced by hydroxyanisole. J Pathol 1970; 101:163-169. Frenk E. Experimentelle Depigmentierung der Meerschweinchenhaut durch selektiv toxische Wirkung von Hydrochinon-monoathylather auf die Melanocyten. Arch Klin Exp Dermatol 1969; 235: 16--24. Pawele JK, Korner A, Bergstrom A. New regulator of melanin biosynthesis and the autodestruction of melanoma cells. Nature 1980; 285:617-619. Schallreuter K, Levenig C. Keratinocyte involvement in the pathophysiology of vitiligo. J Invest Dermatol1991; 96:1024. Schallreuter K, Wood J, Berger J. Low catalase levels in the epidelmis of patients with vitiligo. J Invest Dermatol 1991; 97:1081. Schallreuter K, Pittelkow M. Defective calcium uptake in keratinocyte cell cultures from vitili.ginous skin. Arch Dermatol Res 1988; 280: 137-139. Schallreuter K, Wood KU, Wood J. Control of melanogenesis in the human epidermis by the redox-status of tetrahydrobiopterins. Pteridines 1995; 6: 104107. Maresca V, Rocella M. Increased sensivity to peroxidative agents as a possible pathogenetic factor of melanocyte damage in vitiligo J Invest Dermatol 1977; 109:310-313. Schallreuter K, Moore J, Wood JM. In vivo and in vitro evidence for hydrogen peroxide (H 20 z) accumulation in the epidermis of patients with vitiligo and its successful removal by a DYB activated pseudocatalase. J Invest Dermatol 1999; 4:91-96. Schallreuter K, Pittelkow M, Wood J. EF-Hands calcium binding regulates the thioredoxin reductasejthioredoxin electron transfer in human keratinocytes. Biochem Biophys Res Commun 1989; 162:1311-1316. Yada Y, Higuchi K, lmokawa G. Effects of endothelins on signal transduction and proliferation in human melanocytes. J Bioi Chem 1991; 266: 1835218357.


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Imokawa G, Yada Y, Miyagishi M. Endothelins secreted from human keratinocytes are intrinsic mitogens for human melanocytes. J Bioi Chem 1992; 267:24675-24680. Yohn J, Morelli J, Walchak S. Cultured human keratinocytes synthesize and secrete endothelin-l. J Invest Dermatol 1993; 100:23-26. Schallreuter KU, Wood JM, Pittelkow MR. Regulation of melanin biosynthesis in the human epidermis by tetrahydrobiopterin. Science 1994; 263: 14441446. Schallreuter KU, Wood JM, Lemke KR. Defective tetrahydrobiopterin and cathecolamine biosynthesis in the depigmentation disorder vitiligo. Biochim Biophys Acta 1994; 1226:181-192. Dunerva SG. Changes in the content of adrenaline and noradrenaline in the blood of patients with vitiligo. Vestn Dermatol Venereol 1973; 10:33-36. Morrone A, Picardo M. De Luca C Cathecolamines and vitiligo. Pigment Cell Res 1992; 5:62-69 Davis MD, Ribeiro P. Tipper J. '7-Tetrahydrobiopterin, a naturally occurring analogue of tetrahydrobiopterin is a cofactor for, and a potential inhibitor of the aromatic amino acid hydroxylases. Proc Natl Acad Sci 1992; 89:1010810113. Logan A. Weatherhead B. Post-tyrosinase inhibition of eumelanogenesis by melatonin in hair follicles in vitro. J Invest Dermatol 1980; 74:47-50. Slominski A, Paus R, Bomirski A. Hypotesis: possible role for the melatonin receptor in vitiligo: discussion paper. J Roy Soc Med 1989; 82:539-541. Koplon BS, Shapiro L. Poliosis overlying a neurofibroma. Arch Dermatol 1968; 98:631-633 Zvulunov A, Esterly NB. Neurocutaneous syndromes associated with pigmentary skin lesion. J Am Acad Dermatol 1995; 32:915-935. Mosher D, Fitzpatrick T, Hori H. Disorders of pigmentation. In: Fitzpatrick T, Eisen A, Wolff K, eds. Dermatology in General Medicine. 4th ed. New York: McGraw-HilL 1998:903-955. Arnozan L. Vitiligo avec troubles nerveus sensitifs et sympathetiques: I'origine sympathique du vitiligo. Bull Soc Franc Dermatol Syphil 1992: 29:338-342. Costea V. Leukoderma patches in the course of traumatic paralysis of the brachial plexus in a subject with insular cavities. Dermatovenereologica 1961; 2:161-1166 Lerner AB. Snell RS, Chanco-Turner ML. Vitiligo and sympathectomy. The effect of sympathectomy and alpha-melanocyte stimulating hormone. Arch Dermatol 1965; 91:390-396. Chanco-Turner ML, Lerner AB. Physiologic changes in vitiligo. Arch Dermatol 1966; 96:269-278. Dutta AK. Dermat D. Non-nervous vascular reactions in vitiligo patches (an experimental study). Indian J Dermatol 1972: 17:29-36. Dutta AK, Mandai SB. A study non-nervous vasoconstrictor responses. Int J DermatoI1972: 11:177-180. AI' Abadie MS, Senior HJ, Bleehen SS. Neuropeptide and neuronal marker studies in vitiligo. Br J Dermatol 1994; 131:160-165.

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Cheng L, Khan M, Mudge A W. Calcitonin gene-related peptide promotes Schwann cell proliferation. J Cell Bioi 1995; 129:789-796. Covelli V, Jirillo E. Neuropeptide with immunoregulatory function: current status of investigations. Functional Neurol 1988; 3:253-261. Rameshwar P, Gascon P, Ganea D. Immunoregulatory effects of neuropeptides: stimulation of interleukin-2 production by substance P. J Neuroimmunol 1992; 37:65-74. Schallreuter KU, Wood JM, Pittelkow MR. Increased monoamine oxidase A activity in the epidermis of patients with vitiligo. Arch Dermatol Res 1996; 288:14-18. Tang A, Eller MS, Hara M, et al. E-cadherin is the major mediator of human melanocyte adhesion to keratinocyte in vitro. J Cell Sci 1994; 107:983992 Horiguchi Y, Furukawa F, Fujita M, et al. Ultrastructural localization of Ecadherin cell adhesion molecule on the cytoplasmic membrane of keratinocyte in vivo and in vitro. J Histochem Cytochem 1994; 42:1333-1340. Symington BE, Takada Y, Carter WG. Interactions of integrins alpha3beta} and alpha2beta\: potential role in keratinocyte intercellular adhesion. J Cell BioI 1993; 120523-535. Rosdah1 IK, Szabo G. Mitotic activity of epidermal melanocytes in UVirradiated mouse skin. J Invest Dermatol 1978; 70: 143-148. Friedman PS, Gilchrest BA. Ultraviolet radiation directly induces pigment production by cultured human melanocytes. J Cell Physiol 1987; 133:88-94. Libow LF, Scheide S. DeLeo VA. Ultraviolet radiation acts as an independent mitogen for normal human melanocytes in culture. Pigment Cell Res 1988; 1:397-401. Stierner U, Rosdahl IK, Augustsson A, et al. UVB irradiation induces melanocytes increase in both exposed and shielded human skin. J Invest Dermatol 1989; 92:561-564. Morelli J. Yohn J, Lyons B, et al. Leukotrienes C4 and D4 as potent mitogens for cultured human neonatal melanocytes. J Invest Dermatol 1989; 93:719722. Halaban R, Ghosh S, Baird A. bFGF is the putative natural growth factor for human meJanocytes. In Vitro 1987; 23:47-52. Halaban R, Ghosh S, Kwon B. bFGF, a natural mitogen for normal melanocytes in culture, i expressed in melanomas. J Invest Dermato1 1987; 88:493. Pittelkow MR, Shipley GD. Serum free growth and growth factor requirements for normal huma~ melanocytes in vitro. J Invest Dermatol 1987; 88: 513 Funasaka Y, Boulton T, Cobb M, et al. C-Kit-kinase induces a cascade of protein tyrosine phosphorylation in normal human melanocytes in response to mast cell growth factor and stimulates mitogen-activated protein kinase but is down-regulated in melanomas. Mol Bioi Cell 1992; 2:197-209. Rubin JS, Chan AM, Bottaro DP, et al. A broad spectrum human lung fibroblast-derived mitogen is a variant of hepatocyte growth factor. Proc Natl Acad Sci USA 1991; 88:415-419


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Balaban R, Rubin 1S, Funasaka Y, et a!. Met and hepatocyte growth factor/ scatter factor signal transduction in normal melanocytes and melanoma cells. Oncogene 1992; 7:2195-2206. Imokawa G, Yada Y, Morisaki N, et a!. Biological characterization of human fibroblast-derived mitogenic factors for human melanocytes. Biochem 1 1998; 330:1235-1239. Pincelli C, Yaar M. Nerve growth factor: its significance in cutaneous biology. 1 Invest Dermatol Symp Proc 1997; 1:31-36. Rodeck U, Berlyn M, Menssen HD, et a!. Metastatic but not primary melanoma cell lines grow in vitro independently of exogenous growth factors. Int 1 Cancer 1987; 40:687-690 Edmonson SR, Russo VC, McFarlane AC, et a!. Interactions between growth hormone, insulin-like growth factor I, and basic fibroblast growth factor in melanocyte growth. 1 Clin Endocrinol Metab 1999; 84:1638-1644. Herlyn M, Rodeck U, Mancianti HD, et al. Expression of melanomaassociated antigens in rapidly dividing human meJanocytes in culture. Cancer Res 1987; 47:3057-3061. Pittelkow MR, Shipley GD. Serum-free culture of normal human melanocyte: growth kinetics and growth factor requirements. 1 Cell Physiol 1989; 140:565576. Morelli 1G, Norris DA Lnfluence of inflammatory mediators and cytokines on human melanocyte function. 1 Invest Dermatol 1993; 100:19Is-195s. Medrano EE, Farooqui 1Z, Boissy RE, et al. Chronic growth stimulation of human adult melanocytes by inflammatory mediators in vitro; implications for nevus formation and initial steps in melanocyte oncognesis. Proc Natl Acad Sci USA 1993; 90: 1790-1794 Morelli 1G, Hake SS, Murphy RC, et al. Leukotriene B4-induced human melanocyte pigmentation and leukotriene C4-induced human melanocyte growth are inhibited by different isoquinoline sulfonamides. 1 Invest Dermatol 1992; 98:55-58 Fossati G, Taramelli D, Balsari A, et a!. Primary but not metastatic melanoma expressing DR antigens stimulate autologous lymphocytes. Int 1 Cancer 1984; 33:591-597 Tomita Y, Iwamoto M, Masuda T, et al. Stimulatory effect of prostaglandin E 2 on the configuration of normal human melanocytes in vitro. 1 D. Investermatol 1987; 89:299-301. Tada A, Suzuki I, 1m S, et al. Endothelin-I is a paracrine growth factor that modulates melanogenesis of human melanocytes and partecipates in their responses to ultraviolet radiation. Cell Growth Differ 1998; 9:575-584. Scott G, Cassidy L, Abdel Malek Z. ('(-MSH and endothelin I have opposing effects on melanocyte adhesion, migration and pp25FAK phosphorylation. Exp Cell Res 1997; 237:19-28. McEwan MT, Parsons PG. Regulation of tyrosinase expression and activity in human melanoma cells via histamine receptors. J Invest Dermatol 1991; 97:868-873.

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Herlyn M, Mancianti ML, Jambrosic J, et al. Regulatory factors that determine growth and phenotype of normal human melanocytes. Exp Cell Res 1988; 179:322-331 Hill S, Bleehen SS, MacNeil S. An investigation of the intracellular messenger systems involved in melanogenesis in B16 melanoma. J Invest Dermatol 1987; 89:323 Chakraborty AK, Funasaka Y, Slominski A, et al. Production and release of proopiomelanocortin (POMe) derived peptides by human melanocytes and keratinocytes in culture: regulation by ultraviolet B. Biochim Biophys Acta 1996; 1313:130-138 Nakazawa K, Nakazawa H, Sahuc F, et al. Effects of calphostin C, specific PKC inhibitor on TPA-induced normal human melanocyte growth, morphology and adhesion. Pigment Cell Res 1996; 1:28-34. Gilchrest BA, Park HY, Eller MS, et al. Mechanism of ultraviolet light induced pigmentation. Photochem Photobiol 1996; 63:1-10. Abdel-Naser MB, Hann SK, Bystryn Jc. Oral psoralen with UVA releases circulating growth factor(s) that stimulates cell proliferation. Arch Dermatol 1997; 133:1530-1533. Romero Graillet C, Aberdam E, Clement M, et al. Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. J Clin Invest 1997; 99:635-642. Fitzpatrick TB, Breathnach AS. Die epidermale Melanin-Einheit-System. Dermatol Wochenschr 1963; 147:481-489. Moretti S, Spallanzani A, Amato L, Hautmann G, et al. Vitiligo and epidermal microenvironment: possible involvement of keratinocyte-derived cytokines. Arch Demlatol 2002; 138:273-274. Valyi-Nagy IT, Herlin M. Regulation of growth and phenotype of normal human melanocyte in culture. In: Nathanson L, ed. Melanoma 5, Series on Cancer Treatment and Research. Boston: Kluwer Academic Publishers, 1991:85-101



10 Free Radical Damage in the Pathogenesis of Vitiligo Mauro Picardo and Maria Lucia Dell' Anna San Gallicano Dermatological Institute, Rome, Italy

INTRODUCTION Several different hypotheses have been proposed to explain the mechanism underlying melanocyte impairment in vitiligo (1-4). Among these, some groups have suggested free radical-mediated damage (5-10). In vitro, ex vivo, and in vivo data have been presented for a shift in the antioxidant/prooxidant ratio responsible for oxidative stress. However, at this time the mechanism of melanocyte disappearance is not fully defined: the possible apoptotic pathway has not been completely demonstrated, and a normal pattern of Bcl2, Bax, p2 I, and p53 expression by melanocytes, even after ultraviolet (UV)-B treatment, has been reported (11). The skin appears to be the target of oxidative stress for two reasons: (a) the location between the external environment and the body makes it an easy target for chemical and physical pro-oxidants and (b) some specific types of cutaneous metabolism generate free radicals (Table I). However, skin is rich in natural defenses against oxidative stress, including small radical trapping, as in the case of vitamins and glutathione (GSH), and enzymes such as superoxide dismutase (SOD), catalase (Cat), glutathione peroxidase (GPx), thioredoxin/thioredoxin reductase, and thioredoxin peroxidase (12,13) (Table 2).


123

124 TABLE 1

Species O2

H2 0 2

Picardo and Dell'Anna

ROS Produced During Cellular Activity Sources NADH deydrogenase Ubiquinone cyt c intersection Xanthine oxidase Aldheyde oxidase NADPH oxidase SOD Nitric oxide synthase Xanthine oxidase 6BH 4 recycling NADPH oxidase Pteridines oxidation MAO-A CoO oxidation TNF-a signal

EXPERIMENTAL EVIDENCE OF CUTANEOUS OXIDATIVE STRESS IN VITILIGO

Vitiligo Melanocytes in Culture In vitro melanocytes from perilesional and uninvolved areas of the vitiligo epidermis show a delay in growth, a failure to restart after trypsinization, and may require catalase (14,15). In the long term, culture morphological modifications, such as dilatation of rough endoplasmic reticulum, circular RER profiles, and membrane-bound compartmentalized melanosomes, have been described. These characteristics do not depend on the phase of the disease or passage number and are not necessarily all present at the same time. These aberrations can then alter the interaction with other epidermal ceJls even in normal areas, and in mouse models the dilated RER is associated with an impairment of protein trafficking, including tyrosinase and RER storage (16). However, in reconstructed epidermis, possibly due to the short term of the culture, morphological or functional alterations in melanocytes or keratinocytes were not found (17). Besides the morphological features, a functional impairment has been reported in vitiligo melanocytes. We found an alteration in the antioxidant pattern with increased SOD and lowered Cat activities, associated with an augmented susceptibility to pro-oxidant agents (7). A localized burst of hydrogen peroxide might affect the heme active site of the enzyme, lowering its activity (18), but it is also possible that as a consequence of the low catalase


TABLE

2

Antioxidant System Components

Antioxidant

..."T1

Property

Activity

Location

(1) (1)

:0

SOD

Cat Lipoic acid system ()

GSH

~

Vitamin E

o

~ (0'

::':3"

CD

GPx

~

GSH reductase

0..

8

MnSOD, tetrameric 80 kDa CuZnSOD, dimeric 32 kDa; constitutive Heme group containing; constitutive Lipoic acid + lipoamide dehydrogenase -y-L-glutamyl-L-cysteinyl-glycine; constitutive Lipid-soluble; lowered by UV; inducible Se-dependent; GPx1 to GPx4 b

2H+ + 20 2'-

2H 20 2

->

->

Mitochondria Cytosol

Co (i' ~

*

Peroxisomes

III

2H 20 + O 2

~

GSH-S-transferase TrxR

Ascorbate CoO

a b C

NADPH-dependent homodimer with Sec in C-terminus motif Gly-Cys-Sec-Gly-COOH Water soluble; inducible Involved in electron flow; lowered by UV before vitamin E; constitutive

0

3

III

to

GSH, Vitamin E, ascorbate and CoO regeneration Free radicals direct scavenger; substrate for GPx. Lipoperoxides reduction

Membrane Mitochondria Mitochondria and cytosol Membrane

2H 20 2 ~ 2H 20 + 02 c ; lipoperoxide reduction GSH regeneration Lipoperoxides and pyrimidine dimer reduction 2H+ + 20 2'- -> H20 2+0 2 ascorbate reduction

Mitochondria and cytosol Mitochondria and cytosol Mitochondria and cytosol Mitochondria and cytosol

Vitamin E reduction Lipoperoxide reduction and vitamin E regeneration

Cytosol Inner mitochondrial membrane

CD ~

III

H20 2 + O 2

MnSOD can be induced by oxidative stress or thioredoxin. GPx isoforms have different locations but all use GSH as substrate. Reduction of hydrogen peroxide to water lowers the hydroxyl radical formation via Fenton reaction.

(1)

:5

\eyfJ§n~mli_fMfn), is produced during the

140

Vaccaro and Guarneri

conversion of L-arginine into L-citrulline (a NADPH-dependent reaction), catalyzed by enzymes belonging to the family of nitric oxide synthase (NOS). Two major isoforms of NOS are known: "constitutive" (c-NOS), further divided into neuronal (n-NOS) and endothelial (e-NOS) types, and "inducible" (i-NOS), involved in the regulation of cell homeostasis and in the modulation of immune and cytotoxic response, respectively (9,10,16). Nitric oxide has important functions, both regulatory and cytotoxic: the former are realized through modifications of transcription factors, cell motility, mitochondrial functions, and apoptosis, while the latter are realized through energetic damage, glycolysis block, destruction of the Krebs cycle and oxidative phosphorylation, inhibition of ATP production and DNA synthesis, and DNA deamination (16). In cutaneous physiopathology the prevalence of its cytotoxic activity over the regulatory one is due, probably, to the concentration of nitric oxide produced, the cell types involved, the stage of the disease, and many other factors. Low levels of nitric oxide generated by c-NOS are thought to be important in signal transduction mechanisms, while high levels produced by i-NOS could play an important role in cytostasis and cytotoxicity and hence in the limitation of Thl-induced tissue damage that occurs in various inflammatory conditions (16,17). Despite the well-known importance of nitric oxide in several physiological and pathophysiological conditions, its role in human melanogenesis is still under investigation. It has been found that in normal skin UVA and UVB induce production of nitric oxide, particularly by keratinocytes and melanocytes, through the activation of c-NOS, leading to an increase in tyrosinase activity and melanin synthesis (paracrine and autocrine mediation of UVinduced melanogenesis) (18). Many inflammatory mediators and cytokines have been demonstrated able to directly affect melanogenesis (4-6), but their site of action and their possible effects on pigment production are not perfectly known. The induction of i-NOS also requires multiple cytokines and endotoxins, including TNFa, IFN)', IL-I, IL-2, IL-6, IL-8, GM-CSF, and LPS (16). Recent studies have demonstrated that normal human melanocytes in culture can express i-NOS when stimulated by LPS/cytokines, suggesting a possible participation of i-NOS in hypopigmentary disorders (19). Cytokines can also induce overproduction of tetrahydrobiopterin, a potent inhibitor of melanin biosynthesis (20) and essential cofactor in enzymatic activity of i-NOS (21,22). Large amounts of nitric oxide could lead to self-destruction of melanocytes (11) and reduce de novo attachment ofmelanocytes to the extracellular matrix (23), causing skin depigmentation (19). This mechanism could be important in vitiligo, where an initial imbalance of epidermal cytokines at sites of lesions could cause tetrahydrobiopterin overexpression and i-NOS activation, with consequent nitric oxide overproduction leading to loss and self-destruction of melanocytes (Fig. 2). Copyrighted Material

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141

FIGURE 2 Confocal image obtained in "depth coding mode" (Iesional skin). Overexpression of i-NOS in basal and suprabasal layers.

However. it is still to be verified whether this complex scenario is due to an immune disturbance, an intrinsic susceptibility of melanocytes, an altered regulatory epidermal milieu. or all these factors. In any case, in vitiligo the inadequate response to nitric oxide represents an event sufficient to induce depigmentation. If vitiligo is really a nitric oxide-mediated disease, the use of NOS inhibitors (24), nitric oxide scavengers (25), or tetrahydrobiopterin inhibitors (22) should be considered in its treatment. However, because of nitric oxide's involvement in many different physiological functions, secondary effects of this approach should be carefully evaluated, especially with regard to its possible toxicity. Further studies are then needed to develop more selective inhibitors in order to achieve better efficacy and fewer collateral effects of this potential treatment.


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Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001; 34:65~77. limbow K, Chen H, Park JS, Thomas PD. Increased sensitivity of melanocytes to oxidative stress and abnormal expression of tyrosinase-related protein in vitiligo. Br 1 Dermatol 2001; 144:55-65 van den Wijngaard R, Wankowicz-Kalinska A, Le Poole C, Tigges B, Westerhof W, Das P. Local immune response in skin of generalized vitiligo patients. Destruction of melanocytes is associated with the prominent presence of CLA + T cells at the perilesional site. Lab Invest 2000; 80: 1299-1309. Gordon PR, Mansur CP, Gilchrest BA. Regulation of human melanocyte growth, dendricity, and melanization by keratinocyte derived factors. 1 Invest Dermatol 1989; 92:565-572 Morelli lG, Norris DA. Influence of inflammatory mediators and cytokines on human melanocyte function. J Invest Dermatol 1993; 100:19IS-195S. Moretti S, Spallanzani A, Amato L, Hautmann G, Gallerani I, Fabiani M, Fabbri P. New insights into the pathogenesis of vitiligo: imbalance of epidermal cytokines at sites of lesions. Pigment Cell Res 2002; I 5:87~92. AI'Abadie MS, Senior HJ, Bleehen SS, Gawkrodger Dl. Neuropeptide and neuronal marker studies in vitiligo. Br J Dermatol 1994; 131:160--165. AI' Abadie MS, Warren MA, Bleehen SS, Gawkrodger Dl. Morphologic observations on the dermal nerves in vitiligo: an ultrastructural study. Int 1 Dermatol 1995; 34:837-840 Knowles RG, Moncada S. Nitric oxide synthase in mammals. Biochem 1 1994; 298:249-258. Lowenstein Cl, Dinerman lL, Snyder SH. Nitric oxide: a physiologic messenger. Ann Intern Med 1994; 120:227-237. Qureshi AA, Lerner LH, Lerner EA. From bedside to the bench and back. Nitric oxide and cutis. Arch Dermatol 1996; 132:889-893. Weller R. Nitric oxide~a newly discovered chemical transmitter in human skin. Br 1 Dermatol 1997; 137:665-672. Bruch-Gerharz D, Ruzicka T, Kolb-Bachofen V. Nitric oxide in human skin: current status and future prospects. 1 Invest Dermatol 1998; 110:1-7. Weller R. Nitric oxide, skin growth and differentiation: more questions than answers? Clin Exp Dermatol 1999; 24:388-391. Ormerod AD, Copeland P, Hay I, et al. The inflammatory and cytotoxic effects of a nitric oxide releasing cream on normal skin. J Invest Dermatol 1999; 113:392-397. Kolb H, Kolb-Bachofen V. Nitric oxide in autoimmune disease: cytotoxic or regulatory mediator? Immunol Today 1998; 19:556-561. Ahmed B, Van Den Oord JJ. Expression of the inducible isoform of nitric oxide synthase in pigment cell lesions of the skin. Br J Dermatol 2000; 142:432-440. Romero-Graillet C, Aberdam E, Clement M, Ortonne JP, Ballotti R. Nitric oxide produced by ultraviolet-irradiated keratinocytes stimulates melanogenesis. 1 Clin Invest 1997; 99:635-642.


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Rocha 1M, Guillo LA. Lipopolysaccharide and cytokines induce nitric oxide synthase and produce nitric oxide in cultured normal human melanocytes. Arch Dermatol Res 2001; 293:245-248. Schallreuter KU, Wood JM, Ziegler I, Lemke KR, Pittelkow MR, Lindsey NJ, Gutlich M. Defective tetrahydrobiopterin and catecholamine biosynthesis in the depigmentation disorder vitiligo. Biochem Biophys Acta 1994: 1226:181192. Sakai N, Kaufman S, Milstein S. Tetrahydrobiopterin is required for cytokineinduced nitric oxide production in a murine macrophage cell line (RAW 264). Mol Pharmacol 1993; 43:6-10. Bune AJ, Brand MP, Heales SJ, Shergill JK, Cammack R, Cook HT. Inhibition of tetrahydrobiopterin synthesis reduces in vivo nitric oxide production in experimental endotoxic shock. Biochem Biophys Res Commun 1996; nO(l): 1319. Ivanova K, Le Poole IC, Gerzer R, WesterhofW, Das PK. Effect of nitric oxide on the adhesion of human melanocytes to extracelluar matrix components. J Pathol 1997; 183:469-476 Hobbs AJ, Higgs A, Moncada S. Inhibition of nitric oxide synthase as a potential therapeutic target. Annu Rev Pharmacol Toxicol 1999; 39:191-220. Fricker SP, Slade E, Powell NA, Vaughan OJ, Henderson GR, Murrer BA, Megson IL, Bisland SK, Flitney FW. Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide-mediated diseases. Br J Pharmacol 1997; 122:1441-1449.



12 Histopathological and Ultrastructural Features of Vitiligo Daniela Massi University of Florence, Florence, Italy

INTRODUCTION

Vitiligo is an acquired, idiopathic, and, in the majority of cases, progressive disorder of the skin characterized by depigmented patches of variable size, which enlarge and coalesce to form extensive areas of leukoderma (1-3). On clinical examination, stable patches of vitiligo appear as completely depigmen ted areas sharply demarcated from the surrounding skin. In expanding lesions, there may occasionally be a rim of erythema at the border and a thin zone of transitory partial depigmentation. Repigmentation may lead to several shades of color within a particular lesion. In the pathogenesis of vitiligo, biochemical (4), neurological (5), and immunological (6) factors appear to be involved to a varying extent according to the clinical subset of the disease. Recently, a "convergence theory" combining all pathogenetic hypotheses, has been suggested. Patients with vitiligo note the loss of color from their skin when the disorder first begins or spreads. There are basically two mechanisms by which the melanin might disappear from the skin and the skin turn white: (1) melanocytes may be absent from depigmented areas, or (2) melanogenesis may have been silenced in melanocytes still present within the lesion. In this regard, there is a long-standing controversy over whether melanocytes in vitiligo lesions are actually lost or are still present but functionally dormant or inactivated. Needless to say, both pathogenesis and response to treatment are Copyrighted Material 145

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dependent on this crucial issue. In this view, the histopathological and ultrastructural investigations undertaken to demonstrate the morphological changes in the skin in patients affected by vitiligo are of outmost importance in order to gain insights into the pathophysiology of the disease. LESIONAL SKIN

The clinical presentation of the disease may be quite variable and complex. Likewise, under the microscope, the histopathological features observed in skin specimens taken from affected patients are not uniform, depending on the site (lesional vs. perilesional vs. normally pigmented, nonlesional skin), type, and duration oflesion under examination. However, most of the earlier studies almost unanimously concluded that long-standing depigmented patches show a complete loss of melanin and absence of melanocytes from the epidermis (Figs. 1-5). To enhance the visualization of melanin synthesis and deposition in the epidermis, the Masson-Fontana silver reduction staining technique (7) was perfomed on split skin obtained from depigmented patches (8) demonstrating the absence of melanin. In addition, histochemical procedures specific for the identification ofmelanocytes have been developed to detect quiescient or inactive melanocytes in tissues. For these histochemical procedures, tissues or cells were fixed or incubated in a buffer solution containing either tyrosine or I-dihydroxyphenylalanine (DOPA), the substrates for melanin reaction products at sites where functional tyrosinase exists, i.e., within the melanosomes located in the cytoplasm of melanocytes. Hu et aI., performing DOPA histochemistry, demonstrated that most vitiligo lesions were DOPA-negative (8). Occasionally, islands of DOPA-positive cells were observed in the vitiliginous skin. These DOPA-positive cells were smaller and less dendritic than normal melanocytes. The authors suggested that these cells likely represented inactive melanocytes. Subsequent studies employing DOPA histochemistry on split vitiligo skin also demonstrated the loss or presence of a few abnormal melanocytes in depigmented areas (9). . In line with these observations, Le Poole et a1. in 1993 published a comprehensive immunohistochemical study using a panel of I polyclonal and 17 monoclonal antibodies directed against melanocytes and concluded that melanocytes are indeed absent within vitiliginous lesions, although in epidermal split-skin preparations residual staining attributed to degenerated melanocytes was occasionally observed (10). In addition, Dippel et a1. demonstrated that the c-kit receptor, a molecule expressed early in melanocyte differentiation, was undetectable in vitiligo skin (II). This finding is consistent with the hypothesis that nonfunctional melanocytes are absent from vitiligo lesions. However, there are some sporadic reports indicating that vitiligo lesions are not fully devoid of melanocytes (12, I3). Also in our experience melanoCopyrighted Material

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FIGURE 1 Normal skin (hematoxylin and eosin). Epidermal melanocytes appear as clear cells in and immediately beneath the basal cell layer. Nuclei of melanocytes are smaller and more deeply basophilic than those of contiguous keratinocytes. Melanin is present at all levels of the epidermis, but the basal cell layer is the most heavily pigmented.

FIGURE 2 Perilesional skin (Giemsa). Melanocytes are absent from the basal cell layer while melanin is still p~~dtM~J<eratinocytes.

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FIGURE 3 Perilesional skin (S-100). S-100 immunohistochemical expression shows absence of melanocytes, whereas suprabasal Langerhans cells are evident.

FIGURE 4 Normal skin (semi-thin section, toluidine blue). Scattered vacuolated melanocytes are present within the epidermis. The clear space is an artifact of fixation.



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FIGURE 5 Lesional skin (semi-thin section, toluidine blue). Melanocytes are absent from the basal cell layer.

cytes may be detected at ultrastructural level and are indeed present in lesional skin from vitiligo patients (unpublished observations) (Figs. 6-8). In particular, Husain et al. showed that enzymatic hydroxylation of tyrosine to DOPA in epidermal homogenates of vitiligo was due to the presence of tyrosinase (12). Such residual amounts of the melanocyte-specific enzyme tyrosinase detected in lesional vitiligo provided evidence for the presence ofmelanocytes within lesional skin. A more recent study reported that although in 1- to 3year-old vitiligo lesions neither active or inactive melanocytes are found, nonnegligible amounts of melanin were detected in a few keratinocytes in the basal epidermal layer (14). In particular, late-stage maturation (III/IV) melanosomes were detected and clumped as melanin granules within basal keratinocytes (14). The authors concluded that melanosomes can persist in keratinocytes for some time after the onset of vitiligo (14). In agreement with these observations, Tobin et al. showed that melanocytes could be isolated and established in vitro from all samples of lesional and normal skin, independent of disease duration and independently from treatment (13). In addition, small amounts of mature melanin granules were observed in the amelanotic skin of vitiligo patients, suggesting that some partially functioning melanocytes must be retained in this disorder. The retention of rare intact melanocytes in lesional skin of vitiligo was therefore taken to support the view that a subpopulation of "resistant" epidermal melanocytes could be present. Copyrighted Material

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FIGURE 6 Normal skin (electron micrograph). Uptake of numerous compound melanosomes released from melanocytes into adjacent keratinocytes.

While these rare melanocytes were usually amelanotic, some contained poorly melanized granules. Interestingly, the authors also found extracellular melanin granules lying free in the interstitial space within both amelanotic and normal epidermis. Since these granules were not always associated with melanocyte cytoplasm or melanocyte dendrites, they could possibly be released by degenerative or partially functioning melanocytes. A premature delivery of pre-melanosomes from melanocytes to keratinocytes or ingestion



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FIGURE 7 Perilesional skin (electron micrograph). Although reduced in number, scattered melanosomes are still observed within rare melanocytes.

of immature melanosomes by keratinocytes after fragmentation/degeneration of melanocytes was postulated (13). It is commonly thought that repigmentation is associated with repopulation of amelanotic areas by the melanocytic reservoir of the hair follicles (15,16). In particular, a combination of hair follicle split-DOPA stains and hair follicle split-scanning electron microscopy demonstrated inactive, DOPA-negative melanocytes in the outer root sheaths of normal hair follicles. These inactive melanocytes are also seen in the outer root sheaths of hair Copyrighted Material

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8 Lesional skin (elecron micrograph). Rare melanocytes are still present, although no melanosomes are seen. Keratinocytes contain numerous bundles of tonofilaments. FIGURE

follicle from vitiliginous patches. Treatment of vitiligo stimulates these inactive melanocytes in the middle and lower parts of the outer root sheaths to divide, proliferate, and migrate upward to the dermal-epidermal junction of overlying skin. Melanocytes then spread to form the pigmented islands clinically visible in repigmented lesions (15,16). However, if rare melanocytes are indeed present also in lesional skin, as recent studies have suggested, it is likely that this is not the only mechanism by which repigmentation occurs. Copyrighted Material


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In one study, Merkel cells were reported to be absent from stable Jesional skin, supporting a neural involvement in vitiligo (17). Conversely, in long-standing patches of vitiligo, Langerhans cells were reported to be normal in number although distributed more basally than usual (18). However, a recent study evaluating Langerhans cell distribution in vitiliginous epidermis by immunohistochemistry demonstrated that there were no topographical differences in the presence of Langerhans cells in lesions, at the border, or in pigmented skin of patients with inflammatory vitiligo (19). Degenerative changes affecting nerves have also been reported. In particular, numerous nerve endings were seen in close contact with the basal lamina (20). On ultrastructural examination, approximately three quarters of all dermal nerves in vitiligo biopsies show an increased thickness of the basal membrane of Schwann cells (21). Furthermore, about half of the abnormal dermal nerves in vitiligo skin showed minor axonal degeneration and nerve regeneration, the latter possibly being a reactive change to earlier axonal damage (21). Overall, these observations suggest that neural factors may play a role in the pathogenesis of the disease. PERILESIONAL SKIN

Data from the literature suggest that the peripheral area of expanding lesions that are clinically hypopigmented rather than fully depigmented usually shows a few melanocytes and some melanin granules within the basal layer of the epidermis, although reduced in number as compared with normal skin (22). At the advancing border of vitiligo patches, melanocytes are often prominent, increased in size, and show long dendritic processes containing melanin granules. In contrast, some reports have described the melanocytes at the border to be histopathologically (9) and ultrastructurally (23) normal. Still to be determined is whether different melanocytes' conditions at the border of the vitiligo patches correlate to the state of the lesions (progressing vs. dormant disease). Boissy and Nordlund have occasionally noticed that melanocytes in the perilesional normally pigmented skin immediately nearby an amelanotic vitiligo lesion exhibit cellular shrinkage and increased nuclear heterochromatin, indicating that these cells might be in the initial stages of apoptosis (24). The authors suggested that, theoretically, keratinocytes could effectively phagocytize fragmented apoptotic melanocytes and carry the debris with them as they migrate up the stratum corneum where they desquamate off the epidermis. Removal of melanocytes undergoing apoptosis by the keratinocyte would be consistent with the lack of prominent inflammation and immune response at the lesional borders of most patients with vitiligo. Keratinocyte damage has also been demonstrated at the edge of the vitiligo lesions. Indeed, f~y1lightfM~Mfltion of the basal cell layer

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associated with a mild lymphohistiocytic infiltrate has been described (23,25,26). Ultra-thin sections have better shown vacuolated keratinocytes and extracellular granul~r material between the melanocytes and the keratinocytes, as well as between keratinocytes themselves, suggesting that the keratinocyte is also affected by the pathological process causing vitiligo (23,27). Fibrillar masses similar to colloid bodies may also be present in the upper dermis and in the basal lamina (20). The border of depigmented areas often shows a scant perivascular lymphohistiocytic infiltrate within the superficial dermis as well as superficial edema. Inflammatory cells are invariably present if there is an inflammatory border on clinical examination. If serial sections are examined, a lymphocyte will be sometimes found in close apposition to a melanocyte at the advancing edge. Erythematous borders are also usually associated with variable teleangectasies. A heavy Iymphohistiocytic infiltrate in the upper dermis is more rarely observed (27). Immunohistochemical studies confirmed a highly significant increase in the number of lymphocytes in epidermis and superficial dermis around the margin of the zone of melanocyte depletion in lesions of vitiligo and have shown that the infiltrate is almost entirely composed ofT cells, many of which are activated (MHC class II + , IFN 'Y + ) (28). In particular, the most intense epidermal T-cell infiltration was detected within 0.6 mm of the edge of the lesion. These observations are consistent with the hypothesis that lesional T cells-rather than circulating antimelanocytic antibody-may be responsible for the supposedly autoimmune, but characteristically patchy destruction of melanocytes in vitiligo. Nevertheless, many of the infiltrating T cells are probably innocent bystanders, recruited from the circulation by upregulated cell-adhesion molecules near sites of melanocytic damage. In three cases of inflammatory vitiligo patients, an immunohistochemical investigation demonstrated that in perilesional dermis CD68 + macro phages are more numerous than in lesional and nonlesional skin (19). CD3 + T cells were significantly increased in perilesional as compared with nonlesional or lesional skin. More importantly, within the epidermal compartment, T cells were substantially more numerous in perilesional skin than in control skin. Such T cells were mainly concentrated where the melanocyte destruction takes place, within the basal layer of the epidermis (19). NORMALLY PIGMENTED NONLESIONAL SKIN

The pigmented skin at di tant sites from depigmented patches has been considered histologically unremarkable, with melanocytes being normal in number and morphology. However, electron microscopic studies have shown that these areas may show signs of melanocytic degeneration in the form of



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intracellular edema and vacuolar formation (23). In addition, it has also been demonstrated that melanocytes in the pigmented skin ofpatients with vitiligo may exhibit ultrastructural abnormalities including dilation of rough endoplasmic reticulum, circular RER profiles, and/or membrane-bound compartments ofmelanosomes (29). However, these abnormal structures in cultured melanocytes were not always concomitantly expressed and could not be associated with any specific clinical feature of vitiligo (29).

CONCLUSIONS The pathogenetic mechanisms by which the melanocytes are lost in vitiligo patients have not been yet unequivocally identified. Likewise, at present some controversies exist concerning the histopathological and ultrastructural features in skin specimens from affected patients. Although earlier studies repeatedly indicated that lesional skin shows an absence of melanin and melanocytes, along with degenerative changes affecting both melanocytes and basal/supra basal keratinocytes, more recent investigations demonstrated that melanocytes are never completely absent in the depigmented epidermis and that these melanocytes maintain the capability of recovering their functionality. Further studies are therefore needed to clarify this highly debated issue that has obvious therapeutic implications.

REFERENCES 1. 2. 3. 4. 5. 6.

7. 8. 9.

]0.

Koranne RV, Sachdeva KG. Vitiligo Int J Dermatol 1988; 27:676-681. Nordlund JJ, Lerner AB. Vitiligo. It is important. Arch Dennatol 1982; 118:5-8. Sharquie KE. Vitiligo. Clin Exp DermatoJ 1984; 9:117-126. Lerner A. On the etiology of vitiligo and gray hair. Am J Med 1971; 51:141147. Ortonne JP, Mosher DB, Fitzpatrick TB. Vitiligo and other hypomelanosis of hair and skin. New York: Plenum Medical Book Co., 1983:1-55. Harning R, Cui J, Bystryn Je. Relation between the incidence and level of pigment cell antibodies and disease activity in vitiligo. J Invest Dermatol 1991; 971078-1080. Masson P. Pigment cells in man. NY Acad Sci Special Publication 1948; 4: 1551. Hu F, Fosnaugh RP, Lesney PF. In vitro studies on vitiligo. J Invest Dermatol 1959; 33:267-280. Bleehen SS. Histology of vitiligo. In: Klaus N, ed. Pigment Cell 5: Part II of Preceedings of the X International Pigment Cell Conference Cambridge, MA. Basel: S. Karger, 1979:54-61. Le Poole IC, van den Wijngaard RM, Westerhof W, Dutrieux RP, Das PK.


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II.

12.

13.

14. 15. 16. 17 ]8.

19.

20.

21. 22. 23.

24. 25. 26. 27.

Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. J Invest Dermatol 1993; 100:816-822. Dippel E, Haas N, Grabbe J, Schadendorf D, Hamann K, Czarnetzki BM. Expression of the c-kit receptor in hypomelanosis: a comparative study between piebaldism, naevus pigmentosus and vitiligo. Br J Dermatol 1995; 132182-189. Husain I, Vijayan E, Ramaiah A, Pasricha JS, Madan NC. Demonstration of tyrosinase in the vitiligo skin of human beings by a sensitive f1uorimetric method as well as by '4C(U)-L-tyrosine incorporation into melanin. J Invest Dermatol 1982; 78243-252. Tobin DJ, Swanson NN, Pittelkow MR, Peters EM, Schallreuter KU. Melanocytes are not absent in lesional skin of long duration vitiligo. J Pathol 2000; 191:407-416. Bartosik J, Wulf HC, Kobayasi T. Melanin and melanosome complexes in long standing stable vitiligo-an ultrastructural study. Eur J Dermatol 1998; 8:95-97. Cui J, Shen LY, Wang Gc. Role of hair follicle in the repigmentation of vitiligo. J Invest Dermatol 1991; 97:410-416 Arrunategui A, Arroyo C, Garcia L, et al. Melanocyte reservoir in vitiligo. Int J Dermatol 1994; 33:484-487. Bose SK. Probable mechanism of loss of Merkel cells in completely depigmented skin of stable vitiligo. J Dermatol 1994; 21:725-728. Birbeck MS, Breathnach AS, Everall JD. An electron microscope study of basal melanocytes and high-level clear cells (Langerhans cells) in vitiligo. J Invest Dermatol 1961; 3751. Ie Poole IC, van den Wijngaard RMJGJ, WesterhofW, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am J Pathol 1996; 148:1219-1228. Morohashi M, Hashimoto K, Good TF, Newton DE, Rist T. Ultrastructural studies of vitiligo, Vogt-Koyanagi pigmenti achromians. Arch Dermatol 1977; 113:755-766. AI'Abadie MS, Warren MA, Bleehen SS. Morphologic observations in the dermal nerves in vitiligo: an ultrastructural study. Int J Dermatol 1995; 34:837-840. Brown J, Winkelmann RK. Langerhans cell in vitiligo: a qualitative study. J Invest Dermatol 1967; 49:386-390. Moellmann G, Klein-Angerer S, Scollay DA, Nordlund JJ, Lerner AB. Extracellular granular material in the normally pigmented epidermis of patients with vitiligo. J Invest Dermatol 1982; 79:321-330. Boissy RE. Histology of vitiliginous skin. Tn: Hann SK, Nordlund JJ, eds. Vitiligo. Oxford: Blackwell Science Ltd., 2000:23-34. Hann SK, Park YK, Lee KG, Choi EH, 1m S. Epidermal changes in active vitiligo. J Dermatol 1992; 19:217-222. Galadari E, Mebregan AH, Hashimoto K. Ultrastructural study of vitiligo. Int J Dermatol 1993; 32:269-271. Bhawan J, Bhutani LK. Keratinocyte damage in vitiligo. J Cutan Pathol 1983; 10:207-212



28.

29.

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al Badri AMT, Todd PM, Garioch 11, Gudgeon J E, Stewart DG, Goudie RB. An immunohistological study of cutaneous lymphocytes in vitiligo. J Pathol 1993; 170:149-155. Boissy R, Liu YY, Medrano EE, Nordlund JJ. Structural aberration of the rough endoplasmic reticulum and melanosome compartmentalisation in long term cultures of melanocytes from vitiligo patients. J Invest Dermatol 1991; 97:395-404



13 Clinical Variants of Vitiligo

Seung-Kyung Hann and Sungbin 1m Korea Institute of Vitiligo Research, Seoul, Korea

CLINICAL VARIANTS OF VITILIGO

Vitiligo may occur on any part of the integument, but the face, dorsum of the hands, axillae, umbilicus, nipples, sacrum, and inguinal regions are the most frequently involved sites, exhibiting two general patterns: unilateral or bilateral. In the previous chapters the most common forms of vitiligo have been described. These include: I.

2.

Localized forms: a. Focal: one or more macules localized in one area not showing zosteriform or segmental pattern b. Segmental form: involving a unilateral segment of the body and stopping abruptly at the midline of the affected segment c. Mucosal form: limited to mucous membranes Generalized forms: a. Universalis: with complete or nearly complete depigmentation b. Vulgaris: with scattered macules c. Acrofacial: involving the distal part of the extremities and the face d. Mixed Copyrighted Material

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In this chapter we will describe the most interesting clinical variants of the disease: the segmental, bilateral segmental, and trichrome forms, vitiligo with raised borders, and blue vitiligo.

SEGMENTAL VITILIGO In 1977, an investigator divided vitiligo into segmental and nonsegmental types. He described segmental vitiligo as depigmented patches confined to a definite dermatome, akin to herpes zoster (I). He proposed that the pathogenesis and clinical manifestation of the two types were different from each other, based on his experiment in which sweat secretion was stimulated by local injection of physisotigmine. The segmental type results from dysfunction of the sympathetic nervous system in the affected skin area, while the nonsegmental type results from an immunological mechanism. The clinical features of vitiligo have been reported by many investigators. However, the study of segmental vitiligo has rarely been reported, and the numbers of patients studied limited. The incidence of segmental type is variable; one group of investigators reported 5% (2), another group reported 27.9% (3), and previous Korean studies showed a range between 5.5 and 161 % (4,5). Vitiligo develops at all ages, but it usually occurs in young people between the ages of 10 and 40. However, according to an epidemiological study reported in 1977 (6), abollt half of the patients developed vitiligo after 40 years of age, which was very different from other clinic-based studies. On the other hand, one group reported that onset of nonsegmental vitiligo could occur at any age, whereas segmental vitiligo generally affected the young. In our report (7), segmental vitiligo developed before 30 years of age in 87.0% of

TABLE

1

Site of Segmental Vitiligo

Site

Men (%)

Women (%)

Total (%)

Head and neck Face Neck Scalp Trunk Chest and abdomen Back Extremities Upper extremities Lower extremities Total

57(62.6) 49(53.8) 7(7.7) 1(1 .1) 21(23.1) 17(18.7) 4(4.4) 13(14.3) 7(7.7) 6(6.6) 91

87(65.9) 65(49.2) 20(15.2) 2(1.5) 34(25.8) 31 (23.5) 3(2.3) 11 (8.3) 7(5.3) 4(3.0) 132

144(64.6) 114(51.1) 27(12.1) 3(1.4) 55(24.7) 48(21.5) 7(3.1) 24(10.8) 14(6.3) 10(4.5)6 223


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the patients, and 41.3% were younger than 10 years. This is in accord with the report that segmental vitilligo occurs in young people before age 30 (3). The commonly involved sites of vitiligo are exposed areas, such as the face and dorsum of the hand. In our study of segmental vitiligo, the involved sites were the face, trunk, neck, extremities, and scalp, in descending order (Table I). An older study reported that vitiligo occurs as single lesions in 75% of cases (8), which was the situation with 87% of the patients in our study. Dermatomal distribution revealed that the trigeminal nerve (Fig. I) was most frequently involved, followed by the thoracic (Fig. 2), cervical, lumbar, and sacral nerves (Table 2).

FIGURE 1 Segmental vitiligo distributed in ophthalmic and maxillary branches of trigeminal dermatome. Copyrighted Material

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FIGURE 2

Segmental vitiligo distributed along thoracic dermatome.

We appraised whether hand dominancy has any relation with vitiligo involving the right or left side of the body, but there was no significant relationship between these two factors. The left side was slightly more involved, regardless of the dominant hand. Poliosis, known to be associated with vitiligo in 8.9-45% of cases, occurred in 48.6% in our study. The eyebrows and scalp hair were mostly involved (46.7%); this is because when vitiligo involves the face, neck, and scalp, poliosis of the eyebrows and scalp hair is commonly present (67.4%). Physical trauma, sunburn, psychological


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Clinical Variants of Vitiligo TABLE

2

Dermatomal Distribution of Segmental Vitiligo

Dermatome

Men (%)

Women (%)

Total (%)

Trigeminal Cervical Thoracic Lumbar Sacral Total

49(53.9) 12(13.2) 19(20.9) 10(11.0) 1(1.1) 91

65(50.8) 26(20.3) 31 (24.2) 4(3.1) 2(1.6) 128

114(52.1) 38(174) 50(22.8) 14(64) 3(14) 219

stress, inflammation, pregnancy, contraceptives, etc. are known to be the precipitating factors of vitiligo. But unlike other reports, there was nothing particularly worth mentioning except for sunburn, trauma, and pregnancy. Family history was present in 11.5%, compared to the 7.4% reported by one group (5) and 12% by another (9). A pair of investigators claimed that segmental vitiligo is not associated with other autoimmune diseases (2), but another group found that they were associated in about 9.5% of cases (5). One group of investigators asserted that an autoimmune disease occurred more significantly in nonsegmental vitiligo than in segmental vitiligo and that this difference was due to different pathogenetic mechanisms (3). In our report, association with thyroid diseases, diabetes mellitus, pernicious anemia, and halo nevus, which frequently accompany vitiligo, was seen in 3.4% (7), and this was lower than in the other report (10); however, that could not justify the conclusion that autoimmune mechanisms are restricted to nonsegmental vitiligo, because systemic and topical steroid treatment and psoralen and ultraviolet A (PUVA) therapy can inhibit spreading and induce repigmentation of new lesions of segmental vitiligo, especially on the face (11).

BILATERAL SEGMENTAL VITILIGO The depigmented lesions of segmental vitiligo do not always assume a true dermatomal pattern according to the peripheral nervous system. Not all the patterns of segmental vitiligo follow dermatomal distribution, unlike herpes zoster. Blaschko's lines or acupuncture lines can be applied to the pattern of segmental vitiligo. In our recent study (12), 5 cases of bilateral segmental vitiligo were found among 240 cases of segmental vitiligo, in which the vitiligo lesions appeared on the same or different derma tomes on both sides of the body (Fig. 3). The clinical characteristics of bilateral segmental vitiligo are shown in Table 3. PUVA therapy and steroid treatment could induce repigmentation or stop progression of vitiliginous lesions in bilateral segmental vitiligo. Copyrighted Material

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FIGURE 3 Bilateral segmental vitiligo distributed in linear pattern on both right and left thoracic dermatome. The right side lesions are located at the shoulder and arm; the left side lesions are located at the lower chest and upper abdomen, which do not cross the midline.

Because segmental vitiligo has clinical features that differ from nonsegmental vitiligo, it is quite important to classify the type of vitiligo. The depigmented patches of segmental vitiligo usually remain unchanged for the rest of the patient's life. Therefore, stable segmental vitiligo is a good candidate for epidermal grafting and can be cured almost completely without recurrence. Copyrighted Material


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Clinical Characteristics of Bilateral Segmental Vitiligo Distribution

Patient sex/age

Duration

F/4 F/6 F/8 F/27 F/12

2 4 2 3 2

months yr yr yr yr

Left Chest, Chest, Chest, Chest, Chest,

back, back, back, back, arm

arm arm arm arm

Right

Treatment

Response to treatment

Chest, arm Buttock, thigh Chest, back, arm Chest, back, arm Chest, back, arm

Systemic steroid Topical steroid Topical steroid Systemic PUVA Systemic PUVA

No progression No change Repigmentation Repigmentation Repigmentation

On the other hand, if segmental vitiligo occurs bilaterally, following the same or different dermatomes, it may cause confusion in defining the type of vitiligo. As segmental vitiligo can rarely appear bilaterally following dermatomal distribution, such as in herpes zoster, it may mimic some other type of nonsegmental vitiligo. The clinical course of bilateral segmental vitiligo seems to be the same as unilateral segmental vitiligo.

TRICHROME VITILIGO The term trichrome vitiligo was first suggested in 1964 by Fitzpatrick (13). The lesions have an intermediate zone of hypochromia located between the achromic center and the peripheral unaffected skin. This results in three shades of color-brown, tan, and white-in the same patient (14) (Fig. 4). The trichrome lesion naturally evolves to a typical vitiligo macule. The significance of trichrome is unknown, but it is clearly a metastable or transitional pigmentary state, though it may persist for months to years with little change. Fitzpatrick (13) and Pincus (15) interpreted trichrome as suggestive of a gradual centrifugal spread of hypomelanosis or a stepwise depigmentation. However, other reports pointed out that the sharp demarcation between the three areas in their cases, as well as the lack of gradual changes of color and the stability of the lesion, is inconsistent with the interpretation of trichrome vitiligo as an active centrifugal spreading lesion. Therefore, whether trichrome vitiligo is a temporary phenomenon of active spreading vitiligo or a hypomelanosis showing an unusual progression pattern remained to be defined. However, our recent study (16) showed that trichrome vitiligo is an active, centrifugally spreading lesion through clinico-histopathological studies. The study showed that among the 21 vitiligo patients showing trichrome lesions, 95.2% were classified as having vitiligo vulgaris and 85.7% had spreading lesions clinically. Histopathological findings also showed the characteristics of active spreading vitiligo. Therefore, trichrome vitiligo was regarded as a phenomenon ~pyHl1J:lmMYfe;OO-areas of active vitiligo.

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FIGURE 4 Trichrome vitiligo showing light brown band between vitiliginous and dark brown perilesional skin.

Of the trichrome lesions, 85.5% were localized to the trunk region, including the abdomen, back, and buttock, leading to the assumption that trichrome vitiligo predominates in unexposed skin (Table 4). According to previous reports, sun-exposed areas are the predilection sites of vitiligo and lesions in these areas commonly show rapid progression. In contrast, the fact that trichrome vitiligo lesions predominated in unexposed skin could be one of the reasons the characteristic trichrome features appeared, possibly because of slow progression of the disease. Melanocyte density and skin thickness could also be factors contributing to the development of trichrome features. Blacks have a relatively higher frequency of trichrome vitiligo compared with whites and similarly most of the patients in



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Location of Trichrome Vitiligo

Location

No. of patients (%)

Back Abdomen Buttock Chest Arm Leg Total

12(57) 4(19) 2(9.5) 1(4.8) 1(4.8) 1(4.8) 21(100)

our study had skin type IV or darker. Therefore dark skin also seems to be a contributing factor to the pathogenesis of trichrome vitiligo. The histological findings of trichrome vitiligo showed the most dense distribution of melanin granules in the perilesional normal skin, followed by normal skin, light brown skin, and vitiliginous skin, in descending order. As such, the characteristic trichrome color may be an expression of changes in melanin granules rather than melanocyte numbers. Hyperpigmentation seen around the periphery of white patches is typically found in vitiligo. This was also observed in the trichrome lesions in which perilesional normal skin showed a slightly darker color compared with normal skin and histologically a higher density of melanin granules. Other histological findings such as vacuolar degeneration of the basal cell layer, monon uc1ear cell infiltration of the epidermis and dermis, and melanophage deposition in the dermis were more prominent in light brown skin and perilesional normal skin than in vitiliginous and normal skin. Among these changes, vacuolar degeneration of the basal cell layer and inflammatory cell infiltration were especially accen tuated around the melanocytes in the basal cell layer (Table 5; Fig. 5). However, overall destruction of keratinocytes

TABLE 5

Histological Findings of Trichrome Vitiligo Inflammatory cell infiltration

Vitiliginous skin Light brown skin Perilesional normal skin Normal skin a

Epidermis

Dermis

Vacuolar degeneration of basal cells

1 (4.8)a 13(61.9) 16(762) 2(9.5)

6(28.6) 12(57.1 ) 16(76.2) 3(14.3)

5(23.8) 13(61.9) 19(90.5) 7(33.3)

Number (percentage in parent~f/f»figp,~eifffflfcJ&r7al

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FIGURE 5 Hematoxylin-eosin staining of trichrome vitiligo. Vacuolar degeneration of the basal cell layer and mild inflammatory cell infiltration in epidermis and dermis are more prominent in light brown skin (LBS) and perilesional normal skin (PLNS) than vitiliginous skin (VS) and normal skin (NS) of trichrome vitiligo. (Original magnification x 200.)

coexisted, and we presume that the target of destruction is not limited to melanocytes but also involves keratinocytes as well. Perilesional normal skin shows more severe vacuolar change of the basal layer and inflammatory cell infiltration than light brown skin and histologically is already in the process of vitiligo evolution, despite its normallooking appearance. Therefore, without appropriate treatment, a change clinically into light brown skin can be predicted. Light brown skin clinically and histologically shows features of active vitiligo, although the degree of histological change is subtle compared with perilesional normal skin. The histological features of light brown skin and perilesional normal skin are congruent with findings of active vitiligo lesions of more than 1 year's duration showing vacuolar degeneration of basal cell layer, mononuclear cell infiltration of the epidermis and dermis, and melanophage deposition (17,18). In view of such similarities, trichrome vitiligo could be a variant form of active vitiligo. The number of melanocytes in trichrome vitiligo was greatest in perilesional normal skin followed by light brown skin and vitiliginous skin, with



169

vitiliginous skin showing at least a few melanocytes, albeit less than that of normal skin (Table 6). These results are contradictory with other studies of vitiligo (17,19,20), which report absence of melanocytes in the depigmented patches confirmed by immunohistochemical staining or electron microscopy. The clinical and histological findings of trichrome vitiligo suggest a slower progression of lesions than typical vitiligo, and this could be why melanocytes remain in the white patches. Langerhans cells may playa major immunological role in vitiligo. Interaction between keratinocytes, melanocytes, and Langerhans cells is thought to initiate depigmentation, but the exact mechanism is unknown. In patients with nonsegmental-type vitiligo, a marked depletion of Langerhans cells was noted in active lesions and a repopulation of Langerhans cells was noted in stable lesions (21). In inflammatory vitiligo, an increase in Langerhans cells was observed in adjacent normal skin compared with vitilignous skin and normal skin (22). Our study showed that light brown skin and perilesional normal skin exhibit an increase in Langerhans cell number compared with vitiliginous skin and normal skin (Table 7). From our findings, an increased number of Langerhans cells may be involved in actively spreading vitiligo. Vitiligo lesions of the trunk are known to respond favorably to systemic PUV A therapy in comparison to systemic steroid therapy, and the existence of inactive melanocytes in the epidermis or follicles is a decisive factor influencing treatment results (23,24).

TABLE

6

Numbers of S-100+ Melanocytes in Patients with Trichrome Vitiligo

1 2 3 4 5 6 7 8 9 10 Mean

LBS

VS

Patient no.

5 5 2 4 5 8 8 4 2

± SOb

4.8

± 2.2

14 15 14 8 15 13 8 13 7 11.9 ± 3.3

PLNS

NS

23 a 19 18 13 14 16 15 17 16 11

23

16.8

± 3.0

20 15 16 17 16 12 16 14 16.3 ± 3.5

LBS, light brown skin; NS, normal skin; PLNS, perilesional normal skin; VS, vitiliginous skin. Number of melanocytes per 6 high-power fields (x400). b PLNS and LBS: p < 0.05; LBS and VS: p < 0.05

a


Hann and 1m

170 TABLE 7

Number of CD1a+ Langerhans Cells in Patients with Trichrome

Vitiligo Patient no. 1 2 3 4 5 6 7 8 9 Mean ± SDb

VS

LBS

PLNS

NS

62 a 52 67 28 50 65

36 47 37

14

52 34

73 58 54 44 50 47 60 44 36

295 ± 9.8

55.7 ± 11.1

54.3 ± 10.4

39 36 21 33 34

45 24 31 33 28 36.7 ± 8.6

LBS, light brown skin; NS, normal skin; PLNS, perilesional normal skin; VS, vitiliginous skin. Number of Langerhans cells per 6 high-power fields (x400). b LBS and PLNS compared with VS and NS: p < 0.05.

a

Trichrome vitiligo responded especially well to systemic PUVA treatment. This is because a few melanocytes were still remaining in the white lesions, thereby contributing to the repigmentation process. Therefore, early systemic PUVA therapy should be considered in patients with trichrome features to shorten treatment duration and achieve satisfactory end results. VITILIGO WITH RAISED BORDERS

Generally, vitiligo macules have distinct margins. However, raised borders have, on a few occasions, been observed at the margins of the depigmented borders. This is a rare macroscopic presentation of vitiligo, and only few cases have been reported (25,26). Vitiligo with raised borders has been reported in males and females at any age. The red, raised borders may be present from the onset of vitiligo or may appear several months or years later. A mild pruritus may be present. Histological features of the raised borders show eczematous changes in the epidermis with absence or decrease of melanin pigmentation and fairly dense lymphocytic and histocytic infiltrate in the upper dermis. Complete regression of the red, raised borders has been reported in several patients either spontaneously or after topical steroid therapy. The significance of this localized inflammatory reaction is unknown. According to several histological studies, the presence of a mild lymphocytic



171

infiltrate at the border of active vitiligo may be observed even in the absence of clinical inflammation. Thus, the occurrence of red, raised borders could represent simply an amplification of the usual inflammatory process occurring in vitiligo (26). Inflammatory vitiligo macules with an edematous border and slight scali ness are very unusual. As the inflammatory component disappears, the skin becomes depigmented. It has been suggested that this inflammatory pattern occurs in atopics (27).

BLUE VITILIGO The blue coloration of vitiligo macules has been observed in a patient already affected by postinftammatory hyperpigmentation in whom vitiligo developed. Histological examination of the blue vitiligo lesions showed an absence of epidermal melanocytes and numerous melanophages in the dermis. The blue coloration subsequently disappeared with follicular repigmentation typical of resolving vitiligo (28).

REFERENCES I. 2. 3. 4. 5. 6. 7. 8. 9. 10 II. 12. 13.

Koga M. Vitiligo: a new classification and therapy. Br J Demlatol 1977; 97:255261. EI Mofty AM, EI Mofty M. Vitiligo: a symptom complex. Int J Dermatol 1980; 19:238-247. Koga M, Tango T. Clinical features and course of type A and type B vitiligo. Sr J Dermatol 1988; 118:223-228. Song MS, Hann SK, Ahn PS, Ims, Park YK. Clinical study of vitiligo: comparative study of type A and type B vitiligo. Ann Dermatol 1994; 6:22-30. Park KC, Youn JI, Lee YS. Clinical study of 326 cases of vitiligo. Korean J Dermatol 1988; 26:200-205. Howitz J, Brodthagen H, Schwartz M. Prevalence of vitiligo: epidemiologic survey on the Isle of Borholm, Denmark. Arch Dermatol 1977; 113:47-52. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol 1996; 35:671-674. Lerner AB. On the etiology of vitiligo and gray hair. Am J Med 1971; 51: 147-156. Hann SK, Park YK, Whang KC, Kim HJ Clinical study of 174 patients with generalized vitiligo. Korean J Dermatol 1986; 24:798-805. Park SY, Youn JI, Lim SD. A clinical study of217 cases ofvitiljgo. Korean J Dermato] 1981; 19:145-152. Kim SN, Lee HS, Hann SK. The efficacy of low dose of oral corticosteroids in vitiligo patients. Int J Dermatol 1999; 38:546-550. Lee HS, Hann SK. Bilateral segmental vitiligo. Ann Dermatol1998; 10:129-131. Fitzpatrick TB. Hypomelanosis. South Med J 1964; 57:995-1005.


Hann and 1m

172

14. 15. 16. 17. 18. 19.

20

21. 22.

23. 24. 25. _6. 27. 28.

Fargnoli MC, Bolognia JL. Pentachrome vitiligo. J Am Acad Dermatol 1995; 33853-856. Pincus H. Vitiligo: what is it? J Invest Dermatol 1959; 32:281-284. Hann SK, Kim YS, Yoo JH, Chun YS. Clinical and histopathologic characteristics of trichrome vitiligo. ] Am Acad Dermat01 2000; 42:589-596. Hann SK, Park YK, Lee KG, Choi EH, 1m S. Epidermal changes in active vitiligo. ] Dermatol 1992; 9:217-222. Gokhale BB, Mehta LN. Histopathology of vitiliginous skin. Int J Dermatol 1983; 22:477-480. Le Poole IC, Das PK, van den Wijngaard RM]G], Bose JD, Westerhof W. Review of the etiopathomechanism of vitiligo: a convergence theory. Exp Dermato11993; 2:145-153. Le Poole Ie. van den Wijngaard RMJGF, WesterhofW, Dutrieux RP, Das PK. Presence or absence of melanocytes in vitiligo lesions: an immunohistochemical investigation. ] Invest Dermatol 1993; 100:816-822. Kao CH, Y u HS. Depletion and repopulation of Langerhans cells in nonsegmental type vitiligo. J Dermatol 1990; 17:280-296. Le Poole IC, van den Wijngaard RM]G], WesterhofW, Das PK. Presence ofT cells and macrophages in inflammatory vitiligo skin parallels melanocyte disappearance. Am ] Pa thol 1996; 148: 1219-1228. Ortonne JP, Schmitt D, Thivolet]. PUVA-induced repigmentation of vitiligo: scanning electron microscopy of hair follicles. J Invest Dermatol 1980; 74:40-42. Cui 1, Shen L, Wang G. Role of hair follicles in the repigmentation of vitiligo. 1 Invest Dermatol 1991; 97:410-416. Michaelsson G. Vitiligo with raised borders. Report of two cases. Acta Dermatol Venereol (Stockh) 1968; 48:158-161. Eng AM. Marginal inflammatory vitiligo. Cutis 1970; 6:1005-1008. Ortonne ]P. Special features of vitiligo. In: Hann SK, Nordlund ]1, eds. Vitiligo. Blackwell Science Ltd., 2000:70-75. Ivker R, Goldaber M, Buchness MR. Blue vitiligo. J Am Acad Dermatol 1994; 30829-831.


14 Vitiligo In Children Flora B. de Waard-van der Spek and Arnold P. Oranje Erasmus Me, Rotterdam, The Netherlands

Vitiligo is an acquired idiopathic hypomelanotic disorder characterized by circumscribed depigmented macules resulting from the loss of cutaneous melanocytes. Cutaneous depigmentation is most obvious. However, mucous membranes and eyes may also reveal loss of pigmentation in vitiligo. The general prevalence of vitiligo throughout the world is about I per 200 individuals, and both sexes are affected equally. However, there are locations in the world, such as isolated villages in India, where the prevalence is much higher, as high as 8% (I). There are numerous hypotheses about the etiology of vitiligo, but no data to definitely prove one theory above the other. There are numerous causes for the loss of melanocytes. An autoimmune etiology has been suggested (2). Several observers noted that a number of their patients with vitiligo had other disorders considered to be of autoimmune origin. Such disorders included thyroid and adrenal disease, alopecia areata, and insulin-dependent diabetes mellitus. Furthermore, circulating antibodies an T lymphocytes which react against melanocyte an tigens are present in the sera of a significant proportion of vitiligo patient compared with healthy individuals (2). Recently the melanin-concentrating hormone receptor I (MCHRI) was identified as a novel autoantigen related to vitiligo (3). Vitiligo seems to have a predilection for sibs, although its transmission does not follow Mendelian genetics (l). Other pathogenetic factors mentioned Copyrighted Material

173

de Waard-van der Spek and Oranje

174

are neurological factors, toxic metabolites, and lack of melanocyte growth factor (4). Two known mechanisms for the destruction of cells are necrosis and apoptosis. Recently apoptosis, rather than necrosis, has been hypothesized as the mechanism for removal of melanocytes in vitiligo (5). Apoptosis can be induced by a variety of factors, including immune cytokines, some environmental chemicals, or other molecular mechanisms.

CLINICAL FEATURES OF VITILIGO IN CHILDREN Vitiligo typically begins during childhood or adolescence. Approximately 25% of individuals develop the first signs of cutaneous depigmentation before 10 years of age and 50% before 23 years. Less than 10% of those afflicted develop vitiligo after the age of 42 years (6). Depigmented patches can occur anywhere on the body. Vitiligo is often first noticed as pale maCltles on sun-exposed sites of the face or the dorsal aspects of the hands. The distribution is usually symmetrical and may show a periorificial pattern. Another pattern is unilateral or segmental vitiligo, sometimes in a dermatomal distribution (7). Early or advancing lesions may be partially depigmented and have a freckled appearance or multishaded hue. This is called trichrome vitiligo. As the disease progresses most lesions become completely devoid of pigment. Although vitiligo causes destruction of interfollicular melanocytes, it often spares the follicular pigmented cells. Hairs within patches of vitiligo often remain pigmented, but in older lesions the hairs also become amelanotic. Some patients with vitiligo also have halo nevi. Trauma to the skin can also result in further depigmentation (Koebner phenomenon) (8).

DIFFERENTIAL DIAGNOSIS The diagnosis of vitiligo is made clinically based on the symmetrical distribution of depigmentation developing in most cases in the first two decades of life. The diagnosis can be difficult in the early course. In the differential diagnosis skin diseases like pityriasis alba, pityriasis versicolor, hypopigmented macules like ash leaf spots, albinism, piebaldism, postinflammatory hypopigmentation, leukcoderma, or leprosy in patients immigrating from an endemic area must be kept in mind.

TREATMENT Treatment ofvitiJigo in children requires an approach that manages not only pathophysiological aspects of the disease, but also the psychological and social implications of having a visible skin disorder as vitiligo. Psychological


Vitiligo in Children

175

support is often necessary as the condition can have a profound effect on the self-image of the affected individual (9). A causative treatment is not yet available for vitiligo. Current modalities are directed to stop progression and to achieve repigmentation in order to repair the morphology and functional deficiencies of the depigmented skin areas. Treatment of vitiligo can be divided into nonsurgical repigmentation therapies, autologous transplantation methods, and depigmentation therapies (10). Different sources of ultraviolet (UY) light can be used to stimulate repigmentation either alone ("unsensitized" phototherapy) or in combination with chemicals which are activated by light, as with photochemotherapy. As "unsensitized" phototherapy, broad-band UYB seems only to be moderately effective in treating vitiligo. It is being replaced by narrow-band UYB: the more erythemogenic wavelengths are removed, and wavelengths between 305 and 311 nm are used. This therapy has certain advantages over PUVA (psoralen + UYA) in that no pills are required for treatment and the effects on photocarcinogenesis and photoaging could possibly be reduced (II). A study on the effect of narrow-band UVB therapy in seven patients with vitiligo showed rapid repigmentation in many of them, including those with skin photo types IV and V. This study extended previous observations that narrowband UYB is a useful and well-tolerated treatment option for patients with vitiligo (12). With PUVA therapy, oral or topical, results vary and complete repigmentation is achieved only in a few patients, while cosmetically acceptable improvement is achieved in a majority of the patients. The total number of treatments required is between 50 and 300. PUVA has not been approved for children (11). Phenylalanine is not phototoxic, but the combination of UV light and phenylalanine seems to result in some pigmentation. Reported success rates vary from 14 to 83%. Topical calcipotriol may enhance the effect ofPUVA in the treatment of vitiligo (13,14). Melanocytes are known to express 1,25-dihydroxyvitamin D 3 receptors, and, although their exact role in melanogenesis is not clear, some investigators have suggested that 1,25-dihydroxyvitamin D 3 is involved in the regulation of melanin synthesis (14). Vitamin D 3 is also known to have immunomodulatory effects, which may be an important mechanism of action if vitiligo is considered to be an autoimmune T-cell~mediated disease. Very recently, promising casuistic results have been obtained with application of Taurotimus ointment. The idea of stopping the process causing destruction of melanocytes via the immune hypothesis seems to be very attractive. Growth factors and leukotriens have found to be important in melanocyte proliferation and miCopyrighted Material

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de Waard-van der Spek and Oranje

gration. A possible potential practical use of any of these polypeptides and proteins remains to be determined. Some immunomodulating agents have been successfully used in vitiligo. Topical corticosteroids can be useful for small localized lesions. In an open retrospective assessment comparing the results of treatment of vitiligo with topical steroids in adults and children, using moderately potent to very potent steroids, children appeared to have a better outcome than adults. Younger or darker skinned patients and those with vitiligo affecting the head and neck had better results with topical steroid use than older or paler skinned patients and those with vitiligo affecting other parts of the body (15). Systemic corticosteroids can be very helpful in arresting rapidly spreading disease and can induce repigmentation, but their role in the treatment of vitiligo remains controversial because of the potential for serious side effects (II). Surgical methods intended to repigment leukoderma are a therapeutic option if patients have stable disease. Two types of surgical techniques are available: tissue grafts and cellular grafts, with in-between autologous cultured epithelial grafts. Tissue grafts are full-thickness punch grafts, splitthickness grafts, and suction blister grafts (16). In cellular grafts noncultured keratinocytes and melanocytes or cultured melanocytes can be used. The method with cultured melanocytes is time consuming and requires special laboratory equipment. The first commercially available product in this new field for the treatment of vitiligo is MelanoSeed (Bio Tissue Technologies AG, Freiburg, Germany). This consists of autologous melanocytes, which are cultured in Good Manufacturing Practice (GMP) laboratories certified according EU guidelines. A skin biopsy of healthy well-pigmented skin is taken (full thickness skin). Within 28 days the cell quantity necessary for the transplantation is cultured. The transplantation area is prepared in an optimal way by means of a dennabrasion. After healing the treated vitiligo area can be given narrow-band UVB phototherapy to ensure optimal repigmentation (17). Micropigmentation is another name for tattooing and may be helpful for very stable recalcitrant small lesions. The color often does not match perfectly with the normal skin. In widespread disease with only a few areas of normal pigmented skin, treating the normal skin with depigmentating agents is an option. This is a permanent irreversible process, which can be performed with a depigmentation cream or treatment with the Q-switched ruby laser (II). In a meta-analysis and review of available literature on the nonsurgical repigmentation therapies, class 3 corticosteroids and UV-B were the most effective and safe therapies for localized and for generalized vitiligo, respectively. Considering autologous transplantation methods, no comparative controlled trials were included, so the treatment recommendations for transplantation should be viewed with caution. Split-thickness skin or epi-


177

Vitiligo in Children

dermal blistering grafting can be recommended as the most effective and safest techniques. Only a small number of patients treated with culturing techniques has been studied. Limited data on depigmentation therapies are available: using a depigmentation cream (monobenzone) or using a laser (Q-switched ruby laser). Bleaching with cream take months or years to result in evident signs of depigmentation; laser therapy could give faster results (10). Most of the above-mentioned therapies require many months. There is always the option of using camouflaging cosmetics. The use of sunscreens is also recommended. Sunburn reactions of the depigmented skin will be prevented, and the tanning response of normally pigmented skin will be limited.

PROGNOSIS Depigmented patches remain for life. Partial repigmentation is common in isolated spots of individuals of all ages who have had the disease for variable periods of time. The amount of spontaneous repigmentation is rarely cosmetically sufficient (6).

CONCLUSIONS Vitiligo is an acquired idiopathic hypomelanotic disorder. There are numerous hypotheses about the etiology of vitiligo, but no data to definitely prove one theory above the other. There is no standard treatment. Treatment of vitiligo can be divided into nonsurgical repigmentation therapies, autologous transplantation methods, and depigmentation therapies. Future studies of treatment should also focus on the permanency of the induced repigmentations and the long-term risk-benefit ratios of the modalities.

REFERENCES l.

2. 3.

4. 5.

Nordlund 11. The epidemiology and genetics of vitiligo. Clin Dermatol 1997; 15:875-878. Kemp EH, Waterman EA, Weetman AP. Autoimmune aspects of vitiligo. Autoimmunity 2001; 43(1):65-77. Kemp EH, Waterman EA, Hawes BE, et a!. The melanin-concentrating hormone receptor 1, a novel target of autoantibody responses in vitiligo. 1 Clin Invest 2002; 109(7):923-930. Njoo MD, Westerhof W. Vitiligo. Pathogenesis and treatment. Am 1 Clin Dermatol 2001; 2(3):167-181 Huang CL, Nordlund 11, Boissy R. Vitiligo: a manifestation of apoptosis? Am 1 Clin Dermatol 2002; 3(5):301-308


178 6. 7. 8. 9.

10. II. 12.

13.

14.

15.

16. 17.

de Waard-van der Spek and Oranje Lamerson C, Nordlund 11. Vitiligo. In: Harper JI, Oranje AP, Prose NS, eds. Textbook of Pediatric Dermatology. London: Blackwell Science, 2000:880-891. Shaffrali FCG, Gawkrodger DJ. Management of vitiligo. Clin Exp Dermatol 2000; 25:575-579 Handa S, Kaur 1. Vitiligo: clinical findings in 1436 patients. J Dermatol 1999; 26(10):653-657. Papadopoulos L, Bor R, Legg C. Coping with the disfiguring effects of vitiligo: a preliminary investigation into the effects of cognitive-behavioural therapy. Br J Med Psychol 1999; 72385-396. Njoo MD, Westerhof W, Bos JD, et al. The development of guidelines for the treatment of vitiligo. Arch Dermatol1999; 135:1514-1521. Taneja A. Treatment of vitiligo. J Dermatol Treatm 2002; 13: 19-25. Scherschun L, Kim 11, Lim HW. Narrow-band ultraviolet B is a useful and well-tolerated treatment for vitiligo. J Am Acad Dermatol 2001; 44(6):9991003. Ermis 0, Alpsoy E, Cetin L, et at Is the efficacy of psora len plus ultraviolet A therapy for vitiligo enhanced by concurrent topical calcipotriol? A placebocontrolled double-blind study. Br J Dermatol 2001; 145:472-475. Ameen M, Exarchou Y, Chu AC. Topical calcipotriol as mono therapy and in combination with psoralen plus ultraviolet A in the treatment of vitiligo. Br J Dermatol 200 I; 145:476-479. Cockayne S, Messenger AG, Gawkrodger DJ, et at Vitiligo treated with topical steroids: children with head and neck involvement respond well. J Am Acad Dermatol 2002; 46(6):964-965. Geel N van, Ongenae K, Naeyaert J-M. Surgical techniques for vitiligo: a review. Dermatology 200 I; 202: 162-166. Westerhof W, Lantz W, Yanscheidt W, et at Vitiligo: news in surgical treatment. JEADY 2001; 15:510-511.


15 Vitiligo: Focusing on Clinical Associations with Endocrine, Hematological, Neurological, and Infectious Diseases Alex L1ambrich and Jose Ma Mascaro Hospital Clinic, Barcelona, Spain

INTRODUCTION Vitiligo is a common, acquired, depigmentary disorder of the skin that affects 1-2% of the general population, without racial, sex, or regional differences (1-3). The majority of vitiligo patients are healthy and have no associated pathology, but it is well known that vitiligo occurs in relation to other diseases, mainly linked with the immune system. Since the I960s, numerous reports have tried to prove the association between vitiligo and autoimmune disorders. The clinical observation that 10-15% of patients with autoimmune diseases develop vitiligo in comparison with 1-2 % of the general population (4) and the high prevalence of autoantibodies to melanocytes in the serum of patients with vitiligo (5,6) support the autoimmune hypothesis. Segmental vitiligo, characterized by localized lesions in a dermatomal distribution, seems to be linked less frequently to autoimmune disorders than nonsegmental vitiligo (7,8). A pathogenic mechanism involving a dysfunction of sympathetic nerves in the affected area in segmental type may be the cause for these differences (Fig. 1). Copyrighted Material 179

L1ambrich and Mascaro

180

~

I

VlTILIGO

~--------,

1----. ~--------,

Check: routine blood analyses

Check: associated clinical manifestations

.-----..------~,---,

---I Glycemia

j

Suspect': RheullIlltold arthritis Lupus erytlienilttosus Seronegallve ~pondYloarthritis

Suspect:

1

Myas:tb~Dia

graViS

Antinuclear antibodies Rheumaroidal metor HLA-B27

TSH, T4 Antithyroidal

I

Hemogram

........

antibodies

I

Hyperglycemia

Anemia

I /--"-~OI~~iS [fl Bi.GOT.LOH

~--~

tlYf>'l'Ibyroldlsm:

Qravcs(Uase.

..... .j>.

()

.g ~

'§: CD

0..

~

CD

~

lXJ

Qj' ::l

o

:T

FIGURE

1 Nevus depigmentosus, These congenital nonprogressive hypopigmented macules were

present since birth and stable in size.

-

lD

I II

TABLE 1 Vitiligo

Differential Features of Nevus Depigmentosus, Hypomelanosis of Ito, Tuberous Sclerosis, and Segmental

Localization () 0

"C

~

'§:

Color of lesions Shape

CD

Q.

s:

Course

NO

HI

TS

Birth, rarely early childhood

Birth, early infancy, or childhood

Birth

Unilateral trunk or extremities, lower abdomen

Trunk and extremities

Trunk, legs, arms

Off-white Quasidermatomal macules with irregular margins Stable

Off-white Swirls, streaks, and patches

Dull- to off-white Polygonal, thumbprint,

Evolves and often

Chronic

lance-ovate

tends to remit

Q)

CD

~

Vitiligo: Problems and Solutions

Vitiligo

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