Vitiligo: epidemiology and pathophysiology - Prof.Torello Lotti, MD

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Vitiligo affects 0.5-4% of the World population.
The disease generally begins between the ages of 2 and 40.
In a Dutch study, 50% of patients reported the occurrence before the age of 20.Adults and children of both sex are equally affected
The greater number of reports among females is probably due to greater social consequence to woman and girls affected by this condition.
50% of patients  before the age of 20
25% of patients  before the age of 8
Loss or reduction of melanocytes
Reduced melanine production from melanocytes (altered tyrosinase activity, altered structure/activity of rough endoplasmic reticulum, lack of specific melanocyte receptors…)
Decreased melanine transfer from melanocytes to keratinocytes
Primary disorder of keratinocytes

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  • Genetica: locus di suscettibilità autoimmune sul cromosoma 1, insieme alla suscettibilità per dermatite atopica, alopecia areata e forse altre cose. Immunità:il meccanismo principale è cellulo-mediato. Dopo si smascherano autoantigeni cutanei che montano una risposta anticorpale che rimane in secondo piano, a fare da spettatore innocente (innocent bystander-baistender). Metabolica: squilibrio fra i meccanismi di ossidazione e antiossidazione, con conseguente aumento dei radicali liberi e danno ossidativo sui melanociti. L’ipotesi virale è ormai da scartare.
  • Vitiligo: epidemiology and pathophysiology - Prof.Torello Lotti, MD

    1. 1. Vitiligo: epidemiology and pathophysiology Torello Lotti University Unit of Dermatology - University of Florence School of Medicine Florence, Italy
    2. 2. Vitiligo: Definition <ul><li>Primitive acquired pigmentation disorder with focal depigmentation of the skin </li></ul><ul><li>Characterized by well circumscribed milky white cutaneous/mucous macules </li></ul><ul><li>Patches arise as a consequence of destruction and/or functional inactivation of melanocytes underlying a complex syndrome </li></ul><ul><li>Acquired (only in few cases congenital), often familial (23% of the cases). </li></ul>
    3. 3. Vitiligo: epidemiology <ul><li>Vitiligo affects 0.5-4% of the World population. </li></ul><ul><li>The disease generally begins between the ages of 2 and 40. </li></ul><ul><li>In a Dutch study, 50% of patients reported the occurrence before the age of 20. </li></ul>
    4. 4. Vitiligo epidemiology <ul><li>Incidence ranges from 0,1% to 8,8% in different country of the globe. The highest incidence of the condition has been recorded in India, Mexico and Japan. </li></ul><ul><li>Descriptive epidemiology (incidence, prevalence, HANES 1 study) </li></ul><ul><li>Analytical epidemiology (Factors, Relative risks, odds ratio) </li></ul><ul><li>Clinical epidemiology (Natural history and prognosys) </li></ul>
    5. 5. <ul><li>Adults and children of both sex are equally affected </li></ul><ul><li>The greater number of reports among females is probably due to greater social consequence to woman and girls affected by this condition. </li></ul><ul><li>50% of patients  before the age of 20 </li></ul><ul><li>25% of patients  before the age of 8 </li></ul>Vitiligo epidemiology
    6. 6. Clinical classification <ul><li>Localized </li></ul><ul><ul><ul><li>Focal – one or more macules in one area but not clearly in a segmental distribution </li></ul></ul></ul><ul><ul><ul><li>Unilateral/segmental – one or more macules involving a unilateral segment of the body – lesions stop abruptely at the midline </li></ul></ul></ul><ul><ul><ul><li>Mucosal – mucous membranes alone </li></ul></ul></ul><ul><li>Generalized </li></ul><ul><ul><ul><li>Vulgaris – scattered patches that are widely distributed </li></ul></ul></ul><ul><ul><ul><li>Acrofacialis – distal extremities and face </li></ul></ul></ul><ul><ul><ul><li>Mixed – acrofacialis and vulgaris </li></ul></ul></ul><ul><li>Universalis – complete or nearly complete depigmentation </li></ul>
    7. 7. Vitiligo: why? <ul><li>Loss or reduction of melanocytes </li></ul><ul><li>Reduced melanine production from melanocytes (altered tyrosinase activity, altered structure/activity of rough endoplasmic reticulum, lack of specific melanocyte receptors…) </li></ul><ul><li>Decreased melanine transfer from melanocytes to keratinocytes </li></ul><ul><li>Primary disorder of keratinocytes </li></ul>
    8. 8. Vitiligo etiopathogenesis <ul><li>GENETIC PREDISPOSITION </li></ul><ul><ul><li>Autoimmune Susceptibility Locus (AIS1) </li></ul></ul><ul><li>AUTOIMMUNE </li></ul><ul><ul><li>Umoral mechanism -Autoantibodies </li></ul></ul><ul><ul><li>Citotoxic mechanism – Cell mediated </li></ul></ul><ul><li>METABOLIC </li></ul><ul><ul><li>Hydrogen peroxide accumulation </li></ul></ul><ul><ul><li>Abnormal expression of Tyrosine-Related Protein -1 </li></ul></ul><ul><li>OTHERS </li></ul><ul><ul><li>Viral hypothesis </li></ul></ul><ul><ul><li>Neuronal toxicity </li></ul></ul>
    9. 9. Autoimmune pathogenesis <ul><li>Presence of “vitiligo antibodies” in patients </li></ul><ul><li>Vitiligo is associated with several autoimmune disease (vitiligo is a syndrome, not a disease…): tyroiditis (up to 40%), diabetes type I (1-7%), autoimmune gastritis, autoimmune polyglandular syndromes, alopecia areata… </li></ul><ul><li>Most effective therapies in inducing repigmentation have also immunosuppressive effects (i.e.corticosteroids, ultraviolet, cytotoxic drugs) </li></ul><ul><li>Immunotherapies for melanoma often cause vitiligo patches </li></ul>
    10. 10. Altered antioxidant and scavenger mechanism Increased activity of superoxide dismutase High levels of epidermic 7-BH 4 and H 2 O 2 Inhibition of enzyme function (phenylalanine-hydroxilase and tyrosinase) and abnormal expression of Tyrosinase Related Protein-1 (TRP-1).  impaired melanine synthesis Metabolic pathogenesis
    11. 11. A focus on keratinocytes <ul><li>Impaired scavenging mechanisms can lead to ROS increase and subsequent melanocyte damaging </li></ul><ul><li>Altered function of PAR-2 receptor can impair calcium homeostasis in keratinocytes and affect melanosome intake and processing </li></ul><ul><li>Prignano F, Pescitelli L, Becatti M, Fiorillo C, Taddei N, Lotti T. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – 19th 2008 </li></ul><ul><li>Betts CM, Lotti T, Prignano F. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – 19th 2008 </li></ul>
    12. 12. The focus on keratinocytes <ul><li>The importance of mitochondria in keratinocytes from perilesional skin and the role of oxidative stress </li></ul><ul><li>Prignano F, et al. Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin. J Derm Sci 2009;54:157–167 </li></ul>
    13. 13. Mitochondrial alterations in perilesional keratinocytes <ul><li>Mitochondrial activity plays a crucial role in normal cell function </li></ul><ul><li>Mitochondrial alterations observed in perilesional keratinocytes appear to be very similar to those described in the same cell types during apoptosis </li></ul><ul><li>The mitochondrial damage is associated with an increase in ROS production and, hence, oxidative stress. </li></ul><ul><ul><li>Prignano F, et al. J Derm Sci 2009;54:157–167 </li></ul></ul>
    14. 14. Functional alterations in vitiligo skin <ul><li>High levels of TNF-alpha and FasL in the depigmented epidermis (role in increasing apoptosis) </li></ul><ul><ul><li>Kim NH, et al. J Invest Dermatol 2007;127:2612–7. </li></ul></ul><ul><li>mRNA for TNF- α and IL-6 , with an inhibitory effect on pigmentation, was increased in the epidermis from vitiligo biopsies. </li></ul><ul><li>This could contribute to keratinocyte apoptosis, which results in reduced release of melanogenic cytokines and in melanocyte disappearance. </li></ul><ul><ul><li>Moretti S, et al. Histol Histopathol 2009:24:849-857 </li></ul></ul>
    15. 15. Functional alterations in vitiligo skin <ul><li>Apoptotic keratinocytes may cause a decrease in SCF synthesis, which plays an important role in melanocyte survival and proliferation </li></ul><ul><li>Keratinocyte apoptosis induces a decrease in the synthesis of other melanocyte growth factors, such as bFGF , resulting in melanocyte disappearance. </li></ul><ul><ul><li>Lee AY, et al. Br J Dermatol </li></ul></ul><ul><ul><li>2004;151:995–1003. </li></ul></ul><ul><ul><li>Moretti S, et al. Histol Histopathol </li></ul></ul><ul><ul><li>2009:24:849-857 </li></ul></ul>
    16. 16. Functional alterations in vitiligo skin <ul><li>SCF and ET-1 may contribute to melanocyte survival </li></ul><ul><li>Endothelin-1 (ET-1) mRNA seems to be s ignificantly reduced in lesional as compared to perilesional epidermis </li></ul><ul><ul><li>Moretti S, et al. Histol Histopathol 2009:24:849-857 </li></ul></ul>
    17. 17. Functional alterations in vitiligo skin <ul><li>Protease-activated receptor (PAR) 2 is abundantly expressed by keratinocytes, and seems to contribute to the pigmentation process </li></ul><ul><li>PAR-2 impairment is seen in vitiligo, and may contribute to the epidermal pigment deficit through a reduced melanosome uptake in keratinocytes. </li></ul><ul><li>To date, a precise cause and effect relationship between these two conditions cannot be determined. </li></ul><ul><ul><li>Moretti S, et al. Pigment Cell Melanoma Res 2009;22:335–338 </li></ul></ul>
    18. 18. In search for more evidence: the long road <ul><li>The importance of mitochondria in keratinocytes from perilesional skin and the role of oxidative stress </li></ul><ul><li>The possible role of antioxidant supplementation in the treatment of vitiligo </li></ul>
    19. 19. Positive effects of the supplementation of antioxidants in cultured cells <ul><li>Total Antioxidant Capacity </li></ul><ul><li>(marker of cellular scavenging </li></ul><ul><li>activity) </li></ul><ul><li>Mitochondrial membrane </li></ul><ul><li>depolarization (marker of </li></ul><ul><li>mitochondrial and cellular </li></ul><ul><li>integrity) </li></ul><ul><li>- Becatti M, Prignano F, Fiorillo C, Pescitelli L, Nassi P, Lotti T, Taddei N. The involvement of Smac/DIABLO, p53, NF-kB, and MAPK pathways in apoptosis of keratinocytes from perilesional vitiligo skin: Protective effects of curcumin and capsaicin . Antioxid Redox Signal. 2010, 1;13(9):1309-1321. </li></ul>
    20. 20. Future perspectives <ul><li>Our study group is investigating on the positive effects of the supplementation of antioxidants in cultured cells form lesional, perilesional and healthy skin of selected vitiligo patients. </li></ul><ul><li>The supplementation of curcumin and capsaicin at peculiar concentrations can dramatically improve the resistance of cultured cells to oxidative stress. </li></ul><ul><li>Focus on keratinocytes from perilesional skin as the first actors in vitiligo pathogenesis . </li></ul>
    21. 21. Thank you for your attention professor @ torellolotti.it

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