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Introduction - Vitiligo is the most frequent acquired hypomelanosis, but it's etiology is still uncertain. Many patients conect the onset to physical trauma, stress or illness. Nowadays new thoeries have been undertaken. It is clear that several different processes are involved in the etiology of vitiligo.Aims & Scope - to analyse possible conections between the onset of vitiligo with other associated diseases, that have occurred in our patient’s life. The aim is also to mention about the new theory of the pathogenesis of vitiligo. There are some myths about the vitiligo, because of the misconnection of the vitiligo lesions and that occurs in for example leprosy or in sexually transmitted diseases. That myths have made the vitiligo a stigma in many societies.That problem has also been mention in the presentation. Results - there have been revealed that the onset of vitiligo in this patient may be conected with the prevalence of others autoimmune disorders like thyroid disease, diabetes mellitus, alopecia areata. There was also family history of vitiligo – three patient’s daughters suffered from late onset vitiligo. Additionally there was a significant stress related trigger factor in patient’ life, that could have the influence on the onset of the disease. Comments – Vitiligo is a disorder with a genetic background. The genes of susceptibility to the vitiligo are also connected with other autoimmune disorders. The environmental triggering factors play also a significant role in the onset of the vitiligo. Both melanocytes and nerves arise from a neural crest cells, and this is a basis of the neurohumoral hypothesis of the etiology of vitiligo. Oxidative stress hypothesis is based on a fact that this process may lead to melanocyte destructions and there are high H2O2 levels throughout the epidermidis in patients with vitiligo. The melanocytorragy hypothesis may be the explenation for the Koebner phenomenon in vitiligo. The decreased melanocyte survival hypothesis is associated with the decreased number of tyrosine kinase receptor c-kit in perilesional melanocytes, and with the lower expression of stem cell factor from surrounding keratinocytes. That may lead to vitiligo onset, causing the deficiency in survival signals leading to the melanocyte apoptosis. Questions – 1. Is the Koebner phenomenon connected with the:- Oxidative stress hypothesis - Decreased melanocyte survival hypothesis- Melanocytorragy hypothesis ?2. What play the significant role in the oxidative stress hypothesis :- Elevated levels of tenascin in the vitiligonous skin- Decreased number of tyrosine kinase receptor c-kit in perilesional melanocytes - Low levels of catalase enzyme in the skin of vitiligo patients ?- Disclaimer- This PPT is loaded as student material "as is", from the Vitiligo Master Class Barcelona November 2011; VRF does not endorse or otherwise approve it.
Citation preview
Joanna BobkiewiczUniversity of Medical Sciences in PoznanDepartment and Clinic of Dermatology
Vitiligo etiology – facts, theories and myths – based on a
case report
Taking a history76 year old female
A 25 years history of vitiligo – late onset vitiligo
„Chalk”, pale white macules, different in size and shape
At the beginning - single lesions located in the wrists, the palms and the forearms
Progression of the macules aroud the trunk and the upper and lower limbs
Since 5 years – same lesions on the face – around the eyes, around the mouth, on the forehead
Physical examination
Numerous erosions, crusts and pruritus in the elbows, forearms, and the wrists
Generalized pruritus from several months
From 3 months erythema, then bullae on the upper and lower extremities with severe pruritus
Fotki przedramion
Associated diseasesDiabetes Melitus type 2 for 20 years.
Insulin human: 14-0-6 unitsc/dayGlucose profile: 137-155-181-150 mg/dl
Hypothyroidism for 13 years
Levothyroxinum natricum 100 µg/day The last check-up: TSH 3,78 µU/ul
Alopecia areata 10 years ago
Leukotrichia
Autoimmune theoryUp to 30 % cases conected with thyroid diseaseNumerous of the other autoimmune disorders
associated with vitiligoSkin biopsy – lypmhocytic infiltrates, increased CD
8/ CD 4 ratioSerum IgG antibodies from vitiligo patients are able
to penetrate cultured melanocytes and cause apoptosis
Increased expression in IL-17 and COX-2 genes in vitiligo patiensts’ neutrophils
B.Esmaeili, SA. Rezaee, P. Layegh, J. Tavakkol Afshari, P.Dye, E. Ghayoor Karimiani, F. Kalalinia, H. Rafatpanah
Vagh-Koyanagi-Harada disease occured during pegylated IFN alfa2b and ribavirin therapy J.H. Lim, Y.N. Lee, Y. S. Kim, S.G. Kim, S.W. Jeong, J.Y. Jang, H.S. Kim, S.H. Lee, T.K. Park
Family history3 of Patient’s daughters suffer from
vitiligo
Late – onset vitiligo (the onset of the disease > 50 years old)
One of daughter suffer also from psoriasis, and have very quick progression of the vitiligo lesions
Patient son doesn’t have any vitiligo lesions
Genetic linkage
Vitiligo is inherited in a non-Mendelian, multifactorial, polygenic pattern with incomplete penetrance
HLA haplotypes are thought to correlate with vitiligo susceptibility
1. HLAs – A22. DR-43. DR-7 are the most frequent
Various ethnicities have different HLA – associated susceptibilities
Genetic linkageNumerous candidate genes, genetic loci that are believed to be associated with vitiligo
1. The gene for lymphoid protein tyrosinase phosphatase – regulates T cell activity
2. The NALP-1 – key regulator of the immune system
3. Mannose – binding lectin – when abberant predisposed to infections and autoimmune diseases
These genes and genetic loci can be also associated with numerous autoimmune disorders
Multifactorial etiology Different phenotypes are correlated with various genetic
susceptibility and with different environmental exposure
Autoimmune disorders involves interactions between genetic risk factors and environmental triggering factors
1. Emotional stress2. Exposure to the sun , severe sunburn3. Skin trauma ( Koebnerization ) or4. Drugs, toxins and chemicals (..) may precede the onset
The melanocytes are more susceptible to damage factors than keratinocytes
Interactions between disease – susceptible genes and gene – environment interactions
Stress
Life long history of husband’s disease, that have a strong influence on quality of patient’s life, on the level of emotional stress in her life
This situation also affected patient’s daughters, having the same infulence on their quality of life
The influence of the stress may also be seen in Patients history
Associated diseases
Angina pectoris diagnosed 27 years ago
Myocardial infarction in 1994, 1998, 2008
Hypertension diagnosed 3 years ago
Paroxysmal supraventricular tachycardia
Chronic heart falilure, NYHA scale II
Chronic venosus insufficiency
Breast cancer
Carcinoma mucinosum invasivum of right breast (2005)
Fibroadenoma of left breast (2005)
Surgical resection of breast cancer and following radiotherapy of affected area
Every year check-up – abdominal ultrasonography , mammography
Neurohumoral hypothesis
Dissregulation of the nervous system may lead to the damage of the melanocytes
Both melanocytes and nerves arise from neural crest cells
There are increased epinephrine, norepinephrine and neuropeptyde Y levels in vitiligo lesions ( in immunohistochemical test ) – direct damage, vasoconstriction, hypoxia
In patients with recent onset or progressive disease urine levels of homovanilic and vanillmandelic acid are significantly highA. Alikhan, L.M. Felsten, M. Daly, V. Petronic-Rosic
Sun exposure
In 70’s during seaside the Patient had severe sunburn on the majority of the skin surface. She was covered by clothes during this one day
The vitiligo lesions occur esspecialy in the area with high sun exposure during summer or spring – the dorsal surface of the hands, the face - periorificial
After the Patient gave birth to her first child, she suffered from severe hemmorhagy and she needed an allogenic peripheral blood transplant
58 year old female who was diagnosed with the acute myelogenous leukemia received a HLA-idendtical allogenic peripheral stem cell transplant
After 18 months post transplant she presented with patchy depigmentation of the skin, involving her face, trunk, upper and lower extremities
The donor – her sister – had vitiligo for several years beforeA. Campbell-Fontaine, J.E.Coad, R. Kovach, S.C. Ericson
Newer theoriesOxidative stress hypothesis
1.Both lesional and non-lesional skin from vitiligo patients has abnormally low levels of catalase enzyme, which correlates with high H2O2 levels throughout the epidermidis
2.A single nucleotide polymorphism in the catalase gene is more frequent among the vitiligo patients
3.H₂O₂ acummulation degrades the activity of the catalase enzymeA. Alikhan, L.M. Felsten, M. Daly, V. Petronic-Rosic
Newer theoriesMelanocytorragy hypothesis
1. Melanocytes are weakly anchored – minor friction and/or stress can induce upward migration and loss ( Koebnerization phenomenon )
2. Several minutes of light friction on the nonlesional skin of vitiligo patients produced melanocyte detachment after 4-24h
3. Tenascin – extracellular matrix molecule, inhibiting adhesion of the melanocytes to fibronectin, is elevated in vitiligonous skin. This may contribute to loss of melanocytes, or ineffective repopulationA. Alikhan, L.M. Felsten, M. Daly, V. Petronic-Rosic
Newer theoriesDecreased melanocyte survival hypothesis
1. Significantly decreased number of tyrosine kinase receptor c-kit in perilesional melanocytes
2. Lower expression of stem cell factor from surrounding keratinocytes
3. Keratinocyte-derived stem cell factor regulates melanocytes growth and survival by binding to membrane tyrosine kinase c-kit receptorA. Alikhan, L.M. Felsten, M. Daly, V. Petronic-Rosic
Myths
Poor medical carePersonal behaviourDietState of mindPollutionA sign of leprosyA sign of sexually transmitted
infectionsProfound impact on patients’ self-
esteem, self- image, interpersonal relationship, quality of life !
Hope for melanoma therapy
„The selective destruction of pigment cells that occurs in vitiligo may by therapeutic goal in melanoma research”
„Vitiligo patients might represent a unique source of therapeutic cells, to be used in allotransfer for HLA matched melanoma patients”
„High frequencies of self-reactive T lymphocytes directed toward melanocyte differentation antigens are found in vitiligo patients, might be directly responsible of the disease”
„T lymphocytes specific for different melanocyte differentation antigens are fuond in vitiligo and represent the effective anti-melanocyte reactivity, that is often innefective in melanoma”B. Palremo, S. Garbelli, S. Mantovani, C. Giachino
Thank You for attention