Vitiligo: Vitiligo: epidemiology and epidemiology and pathophysiology pathophysiology Torello Lotti Torello Lotti University Unit of Dermatology University Unit of Dermatology - - University of Florence School University of Florence School of Medicine of Medicine Florence, Italy Florence, Italy
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Vitiligo: epidemiology and pathophysiology - Prof.Torello Lotti, MD
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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Vitiligo: epidemiology and Vitiligo: epidemiology and pathophysiologypathophysiology
Torello LottiTorello Lotti
University Unit of Dermatology - University Unit of Dermatology -
University of Florence School of MedicineUniversity of Florence School of Medicine
disorder with focal depigmentation of disorder with focal depigmentation of the skinthe skin
Characterized by well circumscribed Characterized by well circumscribed milky white cutaneous/mucous maculesmilky white cutaneous/mucous macules
Patches arise as a consequence of Patches arise as a consequence of destruction and/or functional destruction and/or functional inactivation of melanocytes underlying inactivation of melanocytes underlying a complex syndromea complex syndrome
Acquired (only in few cases congenital), Acquired (only in few cases congenital), often familial (23% of the cases).often familial (23% of the cases).
Vitiligo: epidemiologyVitiligo: epidemiology 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.
Vitiligo epidemiologyVitiligo epidemiology
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.
Descriptive epidemiology (incidence, prevalence, HANES 1 study)
Clinical epidemiology (Natural history and prognosys)
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
Vitiligo epidemiologyVitiligo epidemiology
Clinical classificationClinical classification
Localized Focal – one or more macules in one area but not clearly in a segmental
distribution Unilateral/segmental – one or more macules involving a unilateral
segment of the body – lesions stop abruptely at the midline Mucosal – mucous membranes alone
Generalized Vulgaris – scattered patches that are widely distributed Acrofacialis – distal extremities and face Mixed – acrofacialis and vulgaris
Universalis – complete or nearly complete depigmentation
Vitiligo: why? Vitiligo: why?
1. Loss or reduction of melanocytes
2. Reduced melanine production from melanocytes (altered tyrosinase activity, altered structure/activity of rough endoplasmic reticulum, lack of specific melanocyte receptors…)
3. Decreased melanine transfer from melanocytes to keratinocytes
Autoimmune pathogenesisAutoimmune pathogenesis Presence of “vitiligo antibodies” in Presence of “vitiligo antibodies” in
patients patients Vitiligo is associated with several Vitiligo is associated with several
autoimmune disease (vitiligo is a autoimmune disease (vitiligo is a syndrome, not a disease…): tyroiditis (up syndrome, not a disease…): tyroiditis (up to 40%), diabetes type I (1-7%), to 40%), diabetes type I (1-7%), autoimmune gastritis, autoimmune autoimmune gastritis, autoimmune polyglandular syndromes, alopecia polyglandular syndromes, alopecia areata…areata…
Most effective therapies in inducing Most effective therapies in inducing repigmentation have also repigmentation have also immunosuppressive effects immunosuppressive effects (i.e.corticosteroids, ultraviolet, cytotoxic (i.e.corticosteroids, ultraviolet, cytotoxic drugs)drugs)
Immunotherapies for melanoma often Immunotherapies for melanoma often cause vitiligo patchescause vitiligo patches
Altered Altered antioxidant and antioxidant and
scavenger scavenger mechanismmechanism
Increased activity Increased activity of superoxide of superoxide
dismutasedismutase
High levels of epidermic 7-BHHigh levels of epidermic 7-BH44 and and
HH22OO22
Inhibition of enzyme function Inhibition of enzyme function (phenylalanine-hydroxilase and tyrosinase) (phenylalanine-hydroxilase and tyrosinase)
and and abnormal expression of Tyrosinase abnormal expression of Tyrosinase Related Protein-1 (TRP-1).Related Protein-1 (TRP-1).
Impaired scavenging mechanisms can lead to ROS increase and subsequent melanocyte damaging
Altered function of PAR-2 receptor can impair calcium homeostasis in keratinocytes and affect melanosome intake and processing
Prignano F, Pescitelli L, Becatti M, Fiorillo C, Taddei N, Lotti Prignano F, Pescitelli L, Becatti M, Fiorillo C, Taddei N, Lotti T. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – T. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – 19th 2008 19th 2008
Betts CM, Lotti T, Prignano F. 5° Joint meeting of SSSR and Betts CM, Lotti T, Prignano F. 5° Joint meeting of SSSR and SCUR. Otsu, Japan May 17th – 19th 2008SCUR. Otsu, Japan May 17th – 19th 2008
The focus on keratinocytesThe focus on keratinocytes
The importance of mitochondria in keratinocytes from perilesional skin and the role of oxidative stress
Prignano F, et al. Ultrastructural and functional alterations of mitochondria in perilesional vitiligo skin. J Derm Sci 2009;54:157–167
Mitochondrial alterations in Mitochondrial alterations in perilesional keratinocytesperilesional keratinocytes
Mitochondrial activity plays a crucial role in normal cell function
Mitochondrial alterations observed in perilesional keratinocytes appear to be very similar to those described in the same cell types during apoptosis
The mitochondrial damage is associated with an increase in ROS production and, hence, oxidative stress.– Prignano F, et al. J Derm Sci 2009;54:157–167
Functional alterations in vitiligo skinFunctional alterations in vitiligo skin
High levels of TNF-alpha and FasL in the depigmented epidermis (role in increasing apoptosis)– Kim NH, et al. J Invest Dermatol 2007;127:2612–7.
mRNA for TNF-α and IL-6, with an inhibitory effect on pigmentation, was increased in the epidermis from vitiligo biopsies.
This could contribute to keratinocyte apoptosis, which results in reduced release of melanogenic cytokines and in melanocyte disappearance.– Moretti S, et al. Histol Histopathol 2009:24:849-857
Functional alterations in vitiligo skinFunctional alterations in vitiligo skin
Apoptotic keratinocytes may cause a decrease in SCF synthesis, which plays an important role in melanocyte survival and proliferation
Keratinocyte apoptosis induces a decrease in the synthesis of other melanocyte growth factors, such as bFGF, resulting in melanocyte disappearance.– Lee AY, et al. Br J Dermatol
2004;151:995–1003.– Moretti S, et al. Histol Histopathol
2009:24:849-857
Functional alterations in vitiligo skinFunctional alterations in vitiligo skin
SCF and ET-1 may contribute to melanocyte survival Endothelin-1 (ET-1) mRNA seems to be significantly
reduced in lesional as compared to perilesional epidermis– Moretti S, et al. Histol Histopathol 2009:24:849-857
Functional alterations in vitiligo skinFunctional alterations in vitiligo skin
Protease-activated receptor (PAR) 2 is abundantly expressed by keratinocytes, and seems to contribute to the pigmentation process
PAR-2 impairment is seen in vitiligo, and may contribute to the epidermal pigment deficit through a reduced melanosome uptake in keratinocytes.
To date, a precise cause and effect relationship between these two conditions cannot be determined.– Moretti S, et al. Pigment Cell Melanoma Res 2009;22:335–
338
In search for more evidence: the long roadIn search for more evidence: the long road
The importance of mitochondria in keratinocytes from perilesional skin and the role of oxidative stress
The possible role of antioxidant supplementation in the treatment of vitiligo
Positive effects of the supplementation Positive effects of the supplementation of antioxidants in cultured cellsof antioxidants in cultured cells
Total Antioxidant Capacity (marker of cellular scavengingactivity)
Mitochondrial membrane depolarization (marker ofmitochondrial and cellularintegrity)
- 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.
Future perspectivesFuture perspectives 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.
The supplementation of curcumin and capsaicin at peculiar concentrations can dramatically improve the resistance of cultured cells to oxidative stress.
Focus on keratinocytes from perilesional skin as the first actors in vitiligo pathogenesis .
Thank you for your attentionThank you for your attention