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