Clinics in Dermatology (2014) 32, 430–434
Vitiligo as a systemic disease Torello Lotti, MD a , Angelo Massimiliano D'Erme, MD b,⁎ Chair of Dermatology and Venereology, University of Rome “G. Marconi,” Rome, Italy Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Viale Michelangiolo 41, 50100 Florence, Italy a
b
Abstract Vitiligo is an acquired depigmentary skin disorder of unknown etiology. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located on various parts of the body. The involvement of skin melanocytes is the most visible one, but a systemic involvement of melanocytes can be observed. Some types of vitiligo (nonsegmental vitiligo) may also be associated with various diseases, mainly with autoimmune pathogenesis. Vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses, causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. © 2014 Elsevier Inc. All rights reserved.
Introduction Vitiligo is an acquired depigmentary skin disorder of unknown etiology. It is characterized by white macules and patches, often symmetric, whose size increase during time, relating to the loss of functioning melanocytes. Approximately, 0.5% to 1% of the European and American population is affected with no racial or sex differences.1-3 The prevalence ranges from less than 0.1% to more than 8% worldwide. Vitiligo can appear at any time, and it significantly impairs the patients' quality of life.1,3 It is usually asymptomatic. This disease does not target merely the skin: it seems to have a potential to trigger the development of generalized syndromes, mainly linked with the immune system. The first report of vitiligo in association with other diseases was published by Thomas Addison in 1855, in which he described the association of adrenal insufficiency and vitiligo.2,4,5 From then, several systemic diseases, mainly with autoimmune pathogenesis, have been described to be significantly associated with vitiligo. ⁎ Corresponding author. Tel.: +393498451303. E-mail address: [email protected] (A.M. D'Erme). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.011
The clinical observation that 10% to 15% of patients with vitiligo develop autoimmune disease in comparison with the prevalence of 1% to 2% of autoimmune diseases in the general population and the presence of autoantibodies against melanocytes support the autoimmune etiopathogenesis of the disease and characterize a part of the systemic involvement.2,6
Clinical manifestation White macules or patches, surrounded by normal skin, usually involve areas that are normally hyperpigmented, such as the face, hand, periorificial area, nipples, and axillae Leukotrichia often follows a depigmentation of surrounding epidermis. Occasionally, mucosae and internal organs containing melanocytes may be affected. The diagnosis is made clinically. Recently, vitiligo has been classified into localized (focal, unilateral/segmental, and mucosal), generalized (vulgaris, acrofacialis, and mixed), and universal (including also special forms such as trichrome vitiligo, quadrichrome vitiligo, and inflammatory vitiligo) according to the extension of the involved areas.7
Vitiligo, a systemic disease Vitiligo can also be divided into segmental and nonsegmental. The first type matches totally or partially with a cutaneous segment (dermatomal distribution).1,8 It is characterized by white patches with rapid onset and involvement of the hair follicle pigmentary system. This form is related probably to a dysfunction of the sympathetic nerves.8 The second type of disease seems to be more associated with systemic involvement.9,10
Systemic involvement The presence, morphology, distribution, and function of melanocytes and melanoblasts in the epidermis and in the hair bulb and buldge area are naturally and commonly investigated by dermatologists and skin biologists. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located spread on the body: skin, hair follicle, mucous membranes, leptomeninges, eye (uveal tract and retinal pigmented epithelium), inner ear (cochlea, vestibular system, utricle, ampullae), and adipocytes. Little information is presently available on melanocytes located in extra-cutaneous organs, even if the presence and functions of melanocytes have already been shown or hypothesized. The involvement of skin melanocytes is the most visible one but a systemic involvement of melanocytes can be observed. This requires a multidisciplinary diagnostic approach.2 Usually, abnormalities of the melanocytes at eyes or at ears do not bring any relevant sign to the patient and are not observed by physicians; however, their involvement in vitiligo provides a high theoretic and pathogenetic interest. Eye-uveal, well differentiated melanocytes (containing both eu- and pheomelanin) are present in the choroid, where they are responsible for constitutive eye pigmentation and for protection against UV radiation. These cells play important roles in the degradation of toxic derivates. Retinal pigment epithelium is formed by a distinct type of melanocytes specifically present as a single layer of cells behind the retina. These melanocytes are involved in the metabolism of retinoids and of rod outer segments, with major implication in vision. Vitiligo can be linked to pigmentary changes, mainly in the fundus, causing atrophic spot in the retinal pigmented epithelium or chorioretinal scars. It is worthy to underlie the involvement of the spectrum of wellknown ocular diseases associated with depigmented skin patches and the systemic symptoms with leptomeningeal or ear pigment cells. These phenomena may be present in different diseases, such as Vogt-Koyanagi-Harada, birdshot retinopathy, sympathetic ophthalmia and melanoma-associated vitiligo, and retinopathy.
431 Melanocytes can be also found in the inner ear, mainly in the vascular streak of the cochlea, where they are required for the generation of endolymph-mediated action potential necessary for normal hearing. In the inner ear, they have a well studied but partially still obscure role in balance. Audiologic studies among vitiligo patients provide contrasting results.2 The presence of hypoacusis due to alteration of melanocytes may be present in individuals affected by piebaldism. Melanocytes are also present in the brain and in the leptomeninges, possibly with different neuroendocrine functions. They are considered relevant in sleeping regulation and in the synthesis and release of central chemosensor(s) generating the respiratory rhythm. Melanocytes in the brain produce the neuromelanin, which seems involved in removing ROS and metals toxic for the neurons. Melanocytes are present in the heart, especially in valves and in septa and in the lungs. They are also present in the atrium and in the pulmonary veins, where they may contribute to the electrical signaling and to atrial arrhythmias. Vitiligo may also be associated with several and different diseases as shown in Table 1.3 Several reports have shown the close association between vitiligo and autoimmune disorders.3,11 A controlled study has clearly shown an increased incidence of autoantibodies in vitiligo patients: antinuclear (12.4%), antimicrosomal (7.1%), and antismooth muscle antibodies (25.7%).3,12 The association with autoimmune thyroid disease, either hypothyroidism or hyperthyroidism, Grave's disease and Hashimoto's disease, is the most well established. It is also a common finding in the sera of vitiligo patients thyroid autoantibodies (antithyroid, antithyroglobulin). Depending on the studies, thyroid dysfunction is variable in vitiligo patients. It ranges from 0.5% to 43%. Twenty-four percent of pediatric patients with vitiligo report thyroid disorders.13-16 One Italian study, performed on 15,126 vitiligo patients, reported an incidence of thyroid disease of 18.5%.17 All the studies agree with the higher prevalence of thyroid disease in vitiligo patients than in the general population, in which the prevalence of this disease is 1%.2,3,18,19 The course of vitiligo and autoimmune thyroid disease does not have any predictable relationship. The onset of these two diseases is often separated by more than a decade.20 Vitiligo is also associated with other endocrinologic disorders, such as polyglandular syndrome type I and type II, Addison's disease, hypoparathyroidism, and diabetes mellitus type I.2,3 Hematologic diseases(autoimmune hemolytic anemia, pernicious anemia, and hemolytic anemia) are reported to be associated with vitiligo. The incidence of their association is lower than with thyroid disease.2,3,21,22 An association with psychiatric diseases has been reported. Patients who present with emotional stress and low self-esteem tend to suffer more from anxiety and depression disorders.1-3,23 Their quality of life is severely compromised. There is a higher incidence of obsession and
432 Table 1 Disorders and syndromes possibly associated with vitiligo (in alphabetical order) (adapted from Alikhan et al.) 3 Less common associations: - Acrokeratosis paraneoplastica of Bazex - Alezzandrini syndrome - APECED syndrome (Autoimmune polyendocrinopathy candidiasis ectodermal dysplasia) - Asthma - Ataxia-telangiectasia - Deafness - Dermatitis herpetiform - DOPA-responsive dystonia - Dysgammaglobulinemia - Hepatitis C - HIV - Inflammatory bowel disease - Kabuki syndrome - Kaposi sarcoma - Lichen ruber planus - Myasthenia gravis More common associations: - Addison's disease - Alopecia areata - Atopic dermatitis - Atrophic gastritis - Autoimmune thyroid disease - Chronic urticaria - Diabetes mellitus - Halo nevi - Hemolytic anemia (autoimmune) - Hypoacusis - Hypoparathyroidism - Ichthyosis - Lymphoma - Melanoma - Metabolic syndrome - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome - Morphea - Multiple sclerosis - Myasthenia gravis - Nail dystrophy - Nonmelanoma skin cancer - Ocular abnormalities - Pemphigus vulgaris - Pernicious anemia - Polyendocrinopathy - Psoriasis - Rheumatoid arthritis - Sarcoidosis - Schmidt syndrome - Systemic lupus erythematosus - Turner syndrome - Twenty-nail dystrophy - Vogt–Koyanagi–Harada syndrome
T. Lotti, A.M. D'Erme phobia among vitiligo patients, especially in those presenting markers of autoimmune diseases.23 Several additional skin diseases are associated with vitiligo. Some of them, such as alopecia areata, dermatitis herpetiformis, and morphea may be associated with vitiligo by a common pathogenic mechanism. On the contrary, atopic dermatitis, psoriasis, and lichen planus have been incidentally present in patients with vitiligo.2,3 There is an interesting association that appears between vitiligo and melanoma. The development of vitiligo in patients with metastatic melanoma can lead to a more favorable prognosis. Recent research has suggested that the immune system, responding to malignant pigmented cells, may also destroy the normal skin melanocytes. In patients with metastatic melanoma, antibodies to melanocytes have been shown.2,3,23-27 Recently, there is growing evidence that vitiligo can also be related to systemic inflammatory disorders, such as obesity and the metabolic syndrome. The last is characterized by a combination of abdominal obesity, glucose intolerance, diabetes mellitus, dyslipidemia, and hypertension.28-31 The association of vitiligo with glucose intolerance, insulin resistance, lipid abnormalities, and hyperhomocysteinemia, also characterizes the systemic involvement of the skin disease.30-32 Regarding the last association, Karadag et al.28,33 has revealed that the levels of homocysteinemia, known to inhibit tyrosinase that participates in melanine synthesis, are higher in the group of vitiligo patients in comparison with the controls; thus, hyperhomocysteine, involved in cardiovascular risks in patients with metabolic syndrome, may represent a risk for those with vitiligo. A recent study has shown that the presence of vitiligo is correlated with a family history of cardiovascular disease.33 Further studies need to clarify the vitiligo association with inflammatory systemic disorders, such as the metabolic syndrome,31 and also the role of melanin in obesity-related pathologies. A role for melanocytes has been recently identified in adipose tissue. Melanin biosynthesis takes place in the visceral adipose tissue of morbidly obese humans. With progression of obesity, adipocytes apparently become more exposed to endogenous apoptotic signals especially ROS-mediated. The melanocytes are believed to have a role in the antiinflammatory reactions and in the antioxidant protection as scavengers of free radicals and reactive oxygen species (ROS).34 Adipocytes may “activate” melanogenesis, thus neutralizing excess ROS levels and reducing oxidative damage. Adipocytic-related melanin production may down regulate the synthesis and the release of proinflammatory cytokines, thus impacting on the common metabolic syndrome. Fasting glucose levels correlate with the total and general output of the melanogenic pathway in the adipose tissue of obese subjects.32 The disturbance of their activity could have systemic consequences, worthy of study.
Vitiligo, a systemic disease
Pathophysiology and pathology of vitiligo as a systemic disease Despite new researches and progress, the pathogenesis of vitiligo is still enigmatic. One or more environmental, physiological, or other triggers might induce localized dysfunction or death of melanocytes in predisposed patients, and genetic studies are noncontributory at the moment.2,35,36 The evaluation of associating HLA antigens or genes in the different ethnic groups affected by vitiligo is not explanatory enough; hence, we have to determine the association between the genetic differences with the age of vitiligo onset and the presence of its comorbidities in several populations to better characterize the pathophysiologic mechanism of vitiligo. The involvement of genetic, immunologic, autoimmunologic, cytotoxic, neuronal, autocytotoxic, biochemical, oxidative, melanocyte, and inflammatory factors have supported by several intriguing but not always proven research. The autoimmune hypothesis remains one of the more interesting hypotheses.2,3,37-40 The proinflammatory cytokines (tumor necrosis factor, interleukin 1, and interleukin 6) and other inflammatory factors (eg, free radicals and reactive oxygen species) are known to be involved28,31 in vitiligo. Their systemic increase may be the result from an autoimmune process, as well as oxidative and cytotoxic activities. Because the etiology and pathogenesis of vitiligo are still unknown or uncertain, the question of whether vitiligo should be classified as a disease or a spectrum of disorders becomes central to its classification and management.3,35 Unfortunately, all vitiligo subjects can be included in one or more groups due to the lack of specific genetic markers or specific characteristics with predictive value for classification and differential diagnosis (Biomarkers).41 At the moment nonsegmental vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. Some patients are affected (or present) only by vitiligo, some others suffer from multisystem organ dysfunction, the “vitiligo systemic syndromes.” Currently, no biomarker can allow us to distinguish the “cutaneous vitiligo” from the “vitiligo as a systemic syndrome.”1,7,38-40 The involvement of other organs (eg, eye and ear) are often asymptomatic at least in the beginning of the disease activity. For this reason, it is crucial to face a patient with vitiligo always as a patient affected by a systemic disease.
Conclusions Multiple research in the last decades has led to a changing view in the genomic, in the pathophysiology, and in the management of the vitiligo. Despite these remarkable
433 advances and high-content clinical and experimental research, there are still details and discrepancies in the understanding of vitiligo.1,7,38-40 The study of the biology of melanocytes beyond the skin offers outstanding information to dermatologists and skin biologists for boosting the complex role of dermatology in general medicine and, more in general, offers unique chances for fertile collaborations with other specialists who may have less information about melanocytes and the biology of melanogenesis. The understanding of the interaction between skin and systemic diseases and the exploration of novel relevant interdependent pathomechanisms melanocytes-centered seem now mandatory.1,7,38-40 The classification of the phenotypic and systemic manifestation with many different clinical presentations, with unknown etiology, few genetic data, different and fragmented pathogenetic hypotheses is very frustrating for the researchers.7 There is an urgent and strong requirement for appropriate molecular markers.7,38-41 At the same time, there are always increasing data to classify vitiligo as a systemic disease.
References 1. Taieb A, Alomar A, Böhm M, et al. The writing group of the Vitiligo European Task Force (VETF) in cooperation with the European Academy of Dermatology and Venereology (EADV) and the Union Européenne desecins Spécialistes (UEMS). Guidelines for the management of vitiligo: The European Dermatology Forum consensus. Br J Dermatol. 2013 Jan;168:5-19. 2. Lotti T, Hautmann G, Hercogovà J. Vitiligo: disease or symptom? From the confusion of the past to current doubts. In: Lotti T, Hercogovà J, eds. Vitiligo. Problems and solutions. New York, NY: Basel: Marcel Dekker, Inc.; 2004. p. 1-14. 3. Alikhan A, Felsten LM, Daly M, Petronic-Rosic V. Vitiligo: a comprehensive overview Part I. Introduction, epidemiology, quality of life, diagnosis, differential diagnosis, associations, histopathology, etiology, and work-up. J Am Acad Dermatol. 2011;65:473-491. 4. Nordlund J, Seung-Kyung H, eds. Vitiligo, A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science; 2000. p. 89-96. 5. Zelissen PM, Bast EJ, Croughs RJ. Associated autoimmunity in Addison's disease. J Autoimmun. 1995;8:121-130. 6. Brostoff J. Autoantibodies in patients with vitiligo. Lancet. 1969;26: 2177-2178. 7. Hercogová J, Schwartz RA, Lotti TM. Classification of vitiligo: a challenging endeavor. Dermatol Ther. 2012;25(Suppl 1):S10-S16. 8. Hann SK, Lee HJ. Segmental vitiligo: clinical findings in 208 patients. J Am Acad Dermatol. 1996;35(5 Pt 1):671-674. 9. Zhang Z, Xu SX, Zhang FY, et al. The analysis of genetics and associated autoimmune diseases in Chinese vitiligo patients. Arch Dermatol Res. 2009;301:167-173. 10. Mazereeuw-Hautier J, Bezio S, Mahe E, et al, Groupe de Recherche Clinique en Dermatologie Pédiatrique (GRCDP). Segmental and nonsegmental childhood vitiligo has distinct clinical characteristics: a prospective observational study. J Am Acad Dermatol. 2010;62:945-949. 11. de Vijlder HC, Westerhof W, Schreuder GM, Claas FH. Difference in pathogenesis between vitiligo vulgaris and halo nevi associated with vitiligo is supported by an HLA association study. Pigment Cell Res. 2004;17:270-274.
434 12. Hann SK, Im S, Kim HI, Kim HS, Lee YJ, Park YK. Increased incidence of antismooth muscle antibody in Korean vitiligo patients. J Dermatol. 1993;20:679-683. 13. Handa S, Kaur I. Vitiligo: clinical findings in 1436 patients. J Dermatol. 1999;26:653-657. 14. Pagovich OE, Silverberg JI, Freilich E, Silverberg NB. Thyroid abnormalities in pediatric patients with vitiligo in New York City. Cutis. 2008;81:463-466. 15. Iacovelli P, Sinagra JL, Vidolin AP, et al. Relevance of thyroiditis and of other autoimmune diseases in children with vitiligo. Dermatology. 2005;210:26-30. 16. Kakourou T, Kanaka-Gantenbein C, Papadopoulou A, Kaloumenou E, Chrousos GP. Increased prevalence of chronic autoimmune (Hashimoto's) thyroiditis in children and adolescents with vitiligo. J Am Acad Dermatol. 2005;53:220-223. 17. Frati R, Frati C, Sassano PP, Antonaci A. Vitiligo, autoimmune thyroiditis: a rare thyroid cancer arising with bone metastates on maxillofacial area. J Exp Clin Cancer Res. 1999;18:85-87. 18. Barona MI, Arrunátegui A, Falabella R, Alzate A. An epidemiologic case-control study in a population with vitiligo. J Am Acad Dermatol. 1995;33:621-625. 19. Hegedüs L, Heidenheim M, Gervil M, Hjalgrim H, Høier-Madsen M. High frequency of thyroid dysfunction in patients with vitiligo. Acta Derm Venereol. 1994;74:120-123. 20. Dittmar M, Kahaly GJ. Polyglandular autoimmune syndromes: immunogenetics and long-term follow-up. J Clin Endocrinol Metab. 2003;88:2983-2992. 21. Gould IM, Gray RS, Urbaniak SJ, Elton RA, Duncan LJ. Vitiligo in diabetes mellitus. Br J Dermatol. 1985 Aug;113:153-155. 22. Moretti S, Arunachalam M, Colucci R, et al. Autoimmune markers in vitiligo patients appear correlated with obsession and phobia. J Eur Acad Dermatol Venereol. 2012 Jul;26:861-867. 23. Grunnet I, Howitz J, Reymann F, Schwartz M. Vitiligo and pernicious anemia. Arch Dermatol. 1970;101:82-85. 24. Bystryn JC, Rigel D, Friedman RJ, Kopf A. Prognostic significante of hypopigmentation in malignant melanoma. Arch Dermatol. 1987;123: 1053-1055. 25. Lerner AB. Melanoma and vitiligo. Cancer Immunol Immunother. 1997 Aug;44:352-354. 26. Nordlund JJ, Kirkwood JM, Forget BM, Milton G, Albert DM, Lerner AB. Vitiligo in patients with metastatic melanoma: a good prognostic sign. J Am Acad Dermatol. 1983 Nov;9:689-696.
T. Lotti, A.M. D'Erme 27. Lindelöf B, Hedblad MA, Sigurgeirsson B. On the association between vitiligo and malignant melanoma. Acta Derm Venereol. 1998 Nov;78: 483-484. 28. Pietrzak A, Bartosińska J, Hercogová J, Lotti TM, Chodorowska G. Metabolic syndrome in vitiligo. Dermatol Ther. 2012;25(Suppl 1): S41-S43. 29. Reich K. The concept of psoriasis as a systemic inflammation: implications for disease management. J Eur Acad Dermatol Venereol. 2012;26(Suppl 2):3-11. 30. Karadag AS, Tutal E, Ertugrul DT. Insulin resistance is increased in patients with vitiligo. Acta Derm Venereol. 2011;91:541-544. 31. Pietrzak A, Lecewicz-Torun' B, Urban J. Comparison of serum lipid in girls affected with vitiligo and control group. Ann Univ Mariae Curie Sklodowska Med. 2000;55:269-274. 32. Rodríguez-Martín M, de Paz NM, Mehtani P, et al. Patients with vitiligo present fewer cardiovascular risk factors: results from a case-control study. J Eur Acad Dermatol Venereol. 2013;27: 124-125. 33. Arunachalam M, Dragoni F, Colucci R, et al. Non-segmental vitiligo and psoriasis comorbidity—a case-control study in Italian patients. J Eur Acad Dermatol Venereol. 2013;26. [Epub ahead of print]. 34. Karadag AS, Tutal E, Ertugrul DT, Akin KO, Bilgili SG. Serum holotranscobalamine, vitamin B12, folic acid and homocysteine levels in patients with vitiligo. Clin Exp Dermatol. 2012;37:62-64. 35. Huggins RH, Janusz CA, Schwartz RA. Vitiligo: a sign of systemic disease. Indian J Dermatol Venereol Leprol. 2006;72:68-71. 36. Majumder PA. Genetics and prevalence of vitiligo vulgaris. In: Hann SK, Nordlund JJ, eds. Vitiligo: A Monograph on the Basic and Clinical Science. Oxford: Blackwell Science Ltd; 2000. p. 18-20. 37. Ongenae K, Van Geel N, Naeyaert JM. Evidence for an autoimmune pathogenesis of vitiligo. Pigment Cell Res. 2003;16:90-100. 38. Lee BW, Schwartz RA, Hercogová J, Valle Y, Lotti TM. Vitiligo road map. Dermatol Ther. 2012;25(Suppl 1):S44-S56. 39. Lotti TM, Hercogová J, Schwartz RA, et al. Treatments of vitiligo: what's new at the horizon. Dermatol Ther. 2012;25(Suppl 1):S32-S40. 40. Valle Y, Lotti TM, Hercogova J, Schwartz RA, Korobko IV. Multidisciplinary approach to R&D in vitiligo, a neglected skin disease. Dermatol Ther. 2012;25(Suppl 1):S1-S9. 41. Biomarkers Definitions Working Group. Biomarkers and surrogate endpoints: preferred definitions and conceptual framework. Clin Pharmacol Ther. 2001;69:89-95.
Vitiligo as a systemic disease Torello Lotti, MD a , Angelo Massimiliano D'Erme, MD b,⁎ Chair of Dermatology and Venereology, University of Rome “G. Marconi,” Rome, Italy Division of Dermatology, Department of Surgery and Translational Medicine, University of Florence, Viale Michelangiolo 41, 50100 Florence, Italy a
b
Abstract Vitiligo is an acquired depigmentary skin disorder of unknown etiology. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located on various parts of the body. The involvement of skin melanocytes is the most visible one, but a systemic involvement of melanocytes can be observed. Some types of vitiligo (nonsegmental vitiligo) may also be associated with various diseases, mainly with autoimmune pathogenesis. Vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses, causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. © 2014 Elsevier Inc. All rights reserved.
Introduction Vitiligo is an acquired depigmentary skin disorder of unknown etiology. It is characterized by white macules and patches, often symmetric, whose size increase during time, relating to the loss of functioning melanocytes. Approximately, 0.5% to 1% of the European and American population is affected with no racial or sex differences.1-3 The prevalence ranges from less than 0.1% to more than 8% worldwide. Vitiligo can appear at any time, and it significantly impairs the patients' quality of life.1,3 It is usually asymptomatic. This disease does not target merely the skin: it seems to have a potential to trigger the development of generalized syndromes, mainly linked with the immune system. The first report of vitiligo in association with other diseases was published by Thomas Addison in 1855, in which he described the association of adrenal insufficiency and vitiligo.2,4,5 From then, several systemic diseases, mainly with autoimmune pathogenesis, have been described to be significantly associated with vitiligo. ⁎ Corresponding author. Tel.: +393498451303. E-mail address: [email protected] (A.M. D'Erme). 0738-081X/$ – see front matter © 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clindermatol.2013.11.011
The clinical observation that 10% to 15% of patients with vitiligo develop autoimmune disease in comparison with the prevalence of 1% to 2% of autoimmune diseases in the general population and the presence of autoantibodies against melanocytes support the autoimmune etiopathogenesis of the disease and characterize a part of the systemic involvement.2,6
Clinical manifestation White macules or patches, surrounded by normal skin, usually involve areas that are normally hyperpigmented, such as the face, hand, periorificial area, nipples, and axillae Leukotrichia often follows a depigmentation of surrounding epidermis. Occasionally, mucosae and internal organs containing melanocytes may be affected. The diagnosis is made clinically. Recently, vitiligo has been classified into localized (focal, unilateral/segmental, and mucosal), generalized (vulgaris, acrofacialis, and mixed), and universal (including also special forms such as trichrome vitiligo, quadrichrome vitiligo, and inflammatory vitiligo) according to the extension of the involved areas.7
Vitiligo, a systemic disease Vitiligo can also be divided into segmental and nonsegmental. The first type matches totally or partially with a cutaneous segment (dermatomal distribution).1,8 It is characterized by white patches with rapid onset and involvement of the hair follicle pigmentary system. This form is related probably to a dysfunction of the sympathetic nerves.8 The second type of disease seems to be more associated with systemic involvement.9,10
Systemic involvement The presence, morphology, distribution, and function of melanocytes and melanoblasts in the epidermis and in the hair bulb and buldge area are naturally and commonly investigated by dermatologists and skin biologists. Vitiligo is not only a disease of melanocytes of the skin. Human melanocytes are derived from the neural crest and are located spread on the body: skin, hair follicle, mucous membranes, leptomeninges, eye (uveal tract and retinal pigmented epithelium), inner ear (cochlea, vestibular system, utricle, ampullae), and adipocytes. Little information is presently available on melanocytes located in extra-cutaneous organs, even if the presence and functions of melanocytes have already been shown or hypothesized. The involvement of skin melanocytes is the most visible one but a systemic involvement of melanocytes can be observed. This requires a multidisciplinary diagnostic approach.2 Usually, abnormalities of the melanocytes at eyes or at ears do not bring any relevant sign to the patient and are not observed by physicians; however, their involvement in vitiligo provides a high theoretic and pathogenetic interest. Eye-uveal, well differentiated melanocytes (containing both eu- and pheomelanin) are present in the choroid, where they are responsible for constitutive eye pigmentation and for protection against UV radiation. These cells play important roles in the degradation of toxic derivates. Retinal pigment epithelium is formed by a distinct type of melanocytes specifically present as a single layer of cells behind the retina. These melanocytes are involved in the metabolism of retinoids and of rod outer segments, with major implication in vision. Vitiligo can be linked to pigmentary changes, mainly in the fundus, causing atrophic spot in the retinal pigmented epithelium or chorioretinal scars. It is worthy to underlie the involvement of the spectrum of wellknown ocular diseases associated with depigmented skin patches and the systemic symptoms with leptomeningeal or ear pigment cells. These phenomena may be present in different diseases, such as Vogt-Koyanagi-Harada, birdshot retinopathy, sympathetic ophthalmia and melanoma-associated vitiligo, and retinopathy.
431 Melanocytes can be also found in the inner ear, mainly in the vascular streak of the cochlea, where they are required for the generation of endolymph-mediated action potential necessary for normal hearing. In the inner ear, they have a well studied but partially still obscure role in balance. Audiologic studies among vitiligo patients provide contrasting results.2 The presence of hypoacusis due to alteration of melanocytes may be present in individuals affected by piebaldism. Melanocytes are also present in the brain and in the leptomeninges, possibly with different neuroendocrine functions. They are considered relevant in sleeping regulation and in the synthesis and release of central chemosensor(s) generating the respiratory rhythm. Melanocytes in the brain produce the neuromelanin, which seems involved in removing ROS and metals toxic for the neurons. Melanocytes are present in the heart, especially in valves and in septa and in the lungs. They are also present in the atrium and in the pulmonary veins, where they may contribute to the electrical signaling and to atrial arrhythmias. Vitiligo may also be associated with several and different diseases as shown in Table 1.3 Several reports have shown the close association between vitiligo and autoimmune disorders.3,11 A controlled study has clearly shown an increased incidence of autoantibodies in vitiligo patients: antinuclear (12.4%), antimicrosomal (7.1%), and antismooth muscle antibodies (25.7%).3,12 The association with autoimmune thyroid disease, either hypothyroidism or hyperthyroidism, Grave's disease and Hashimoto's disease, is the most well established. It is also a common finding in the sera of vitiligo patients thyroid autoantibodies (antithyroid, antithyroglobulin). Depending on the studies, thyroid dysfunction is variable in vitiligo patients. It ranges from 0.5% to 43%. Twenty-four percent of pediatric patients with vitiligo report thyroid disorders.13-16 One Italian study, performed on 15,126 vitiligo patients, reported an incidence of thyroid disease of 18.5%.17 All the studies agree with the higher prevalence of thyroid disease in vitiligo patients than in the general population, in which the prevalence of this disease is 1%.2,3,18,19 The course of vitiligo and autoimmune thyroid disease does not have any predictable relationship. The onset of these two diseases is often separated by more than a decade.20 Vitiligo is also associated with other endocrinologic disorders, such as polyglandular syndrome type I and type II, Addison's disease, hypoparathyroidism, and diabetes mellitus type I.2,3 Hematologic diseases(autoimmune hemolytic anemia, pernicious anemia, and hemolytic anemia) are reported to be associated with vitiligo. The incidence of their association is lower than with thyroid disease.2,3,21,22 An association with psychiatric diseases has been reported. Patients who present with emotional stress and low self-esteem tend to suffer more from anxiety and depression disorders.1-3,23 Their quality of life is severely compromised. There is a higher incidence of obsession and
432 Table 1 Disorders and syndromes possibly associated with vitiligo (in alphabetical order) (adapted from Alikhan et al.) 3 Less common associations: - Acrokeratosis paraneoplastica of Bazex - Alezzandrini syndrome - APECED syndrome (Autoimmune polyendocrinopathy candidiasis ectodermal dysplasia) - Asthma - Ataxia-telangiectasia - Deafness - Dermatitis herpetiform - DOPA-responsive dystonia - Dysgammaglobulinemia - Hepatitis C - HIV - Inflammatory bowel disease - Kabuki syndrome - Kaposi sarcoma - Lichen ruber planus - Myasthenia gravis More common associations: - Addison's disease - Alopecia areata - Atopic dermatitis - Atrophic gastritis - Autoimmune thyroid disease - Chronic urticaria - Diabetes mellitus - Halo nevi - Hemolytic anemia (autoimmune) - Hypoacusis - Hypoparathyroidism - Ichthyosis - Lymphoma - Melanoma - Metabolic syndrome - Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke (MELAS) syndrome - Morphea - Multiple sclerosis - Myasthenia gravis - Nail dystrophy - Nonmelanoma skin cancer - Ocular abnormalities - Pemphigus vulgaris - Pernicious anemia - Polyendocrinopathy - Psoriasis - Rheumatoid arthritis - Sarcoidosis - Schmidt syndrome - Systemic lupus erythematosus - Turner syndrome - Twenty-nail dystrophy - Vogt–Koyanagi–Harada syndrome
T. Lotti, A.M. D'Erme phobia among vitiligo patients, especially in those presenting markers of autoimmune diseases.23 Several additional skin diseases are associated with vitiligo. Some of them, such as alopecia areata, dermatitis herpetiformis, and morphea may be associated with vitiligo by a common pathogenic mechanism. On the contrary, atopic dermatitis, psoriasis, and lichen planus have been incidentally present in patients with vitiligo.2,3 There is an interesting association that appears between vitiligo and melanoma. The development of vitiligo in patients with metastatic melanoma can lead to a more favorable prognosis. Recent research has suggested that the immune system, responding to malignant pigmented cells, may also destroy the normal skin melanocytes. In patients with metastatic melanoma, antibodies to melanocytes have been shown.2,3,23-27 Recently, there is growing evidence that vitiligo can also be related to systemic inflammatory disorders, such as obesity and the metabolic syndrome. The last is characterized by a combination of abdominal obesity, glucose intolerance, diabetes mellitus, dyslipidemia, and hypertension.28-31 The association of vitiligo with glucose intolerance, insulin resistance, lipid abnormalities, and hyperhomocysteinemia, also characterizes the systemic involvement of the skin disease.30-32 Regarding the last association, Karadag et al.28,33 has revealed that the levels of homocysteinemia, known to inhibit tyrosinase that participates in melanine synthesis, are higher in the group of vitiligo patients in comparison with the controls; thus, hyperhomocysteine, involved in cardiovascular risks in patients with metabolic syndrome, may represent a risk for those with vitiligo. A recent study has shown that the presence of vitiligo is correlated with a family history of cardiovascular disease.33 Further studies need to clarify the vitiligo association with inflammatory systemic disorders, such as the metabolic syndrome,31 and also the role of melanin in obesity-related pathologies. A role for melanocytes has been recently identified in adipose tissue. Melanin biosynthesis takes place in the visceral adipose tissue of morbidly obese humans. With progression of obesity, adipocytes apparently become more exposed to endogenous apoptotic signals especially ROS-mediated. The melanocytes are believed to have a role in the antiinflammatory reactions and in the antioxidant protection as scavengers of free radicals and reactive oxygen species (ROS).34 Adipocytes may “activate” melanogenesis, thus neutralizing excess ROS levels and reducing oxidative damage. Adipocytic-related melanin production may down regulate the synthesis and the release of proinflammatory cytokines, thus impacting on the common metabolic syndrome. Fasting glucose levels correlate with the total and general output of the melanogenic pathway in the adipose tissue of obese subjects.32 The disturbance of their activity could have systemic consequences, worthy of study.
Vitiligo, a systemic disease
Pathophysiology and pathology of vitiligo as a systemic disease Despite new researches and progress, the pathogenesis of vitiligo is still enigmatic. One or more environmental, physiological, or other triggers might induce localized dysfunction or death of melanocytes in predisposed patients, and genetic studies are noncontributory at the moment.2,35,36 The evaluation of associating HLA antigens or genes in the different ethnic groups affected by vitiligo is not explanatory enough; hence, we have to determine the association between the genetic differences with the age of vitiligo onset and the presence of its comorbidities in several populations to better characterize the pathophysiologic mechanism of vitiligo. The involvement of genetic, immunologic, autoimmunologic, cytotoxic, neuronal, autocytotoxic, biochemical, oxidative, melanocyte, and inflammatory factors have supported by several intriguing but not always proven research. The autoimmune hypothesis remains one of the more interesting hypotheses.2,3,37-40 The proinflammatory cytokines (tumor necrosis factor, interleukin 1, and interleukin 6) and other inflammatory factors (eg, free radicals and reactive oxygen species) are known to be involved28,31 in vitiligo. Their systemic increase may be the result from an autoimmune process, as well as oxidative and cytotoxic activities. Because the etiology and pathogenesis of vitiligo are still unknown or uncertain, the question of whether vitiligo should be classified as a disease or a spectrum of disorders becomes central to its classification and management.3,35 Unfortunately, all vitiligo subjects can be included in one or more groups due to the lack of specific genetic markers or specific characteristics with predictive value for classification and differential diagnosis (Biomarkers).41 At the moment nonsegmental vitiligo represents a spectrum of many different disorders with different etiologies and pathogeneses causing a common phenotype: the loss of melanocytes and/or their products. This phenotype is always consistent with a systemic involvement. Some patients are affected (or present) only by vitiligo, some others suffer from multisystem organ dysfunction, the “vitiligo systemic syndromes.” Currently, no biomarker can allow us to distinguish the “cutaneous vitiligo” from the “vitiligo as a systemic syndrome.”1,7,38-40 The involvement of other organs (eg, eye and ear) are often asymptomatic at least in the beginning of the disease activity. For this reason, it is crucial to face a patient with vitiligo always as a patient affected by a systemic disease.
Conclusions Multiple research in the last decades has led to a changing view in the genomic, in the pathophysiology, and in the management of the vitiligo. Despite these remarkable
433 advances and high-content clinical and experimental research, there are still details and discrepancies in the understanding of vitiligo.1,7,38-40 The study of the biology of melanocytes beyond the skin offers outstanding information to dermatologists and skin biologists for boosting the complex role of dermatology in general medicine and, more in general, offers unique chances for fertile collaborations with other specialists who may have less information about melanocytes and the biology of melanogenesis. The understanding of the interaction between skin and systemic diseases and the exploration of novel relevant interdependent pathomechanisms melanocytes-centered seem now mandatory.1,7,38-40 The classification of the phenotypic and systemic manifestation with many different clinical presentations, with unknown etiology, few genetic data, different and fragmented pathogenetic hypotheses is very frustrating for the researchers.7 There is an urgent and strong requirement for appropriate molecular markers.7,38-41 At the same time, there are always increasing data to classify vitiligo as a systemic disease.
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