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Vitiligo, Depigmentation and MonobenzoneVITILIGOOccurs worldwide about 1% of the population, mostly between the age of 10-30Chronic skin diseaseOther name = LeukodermaWhite spots occur when the skin no longer forms melanin (pigment that determines the color of your skin, hair, and eyes)The white patches of irregular shapes begin to appear on your skinTotal absence of melanocytes microscopically

Cont.. Associated with three other autoimmune diseases:Addisons DiseaseHyperthyroidismPernicious Anemia

A skin biopsy may be required to rule out the other causes of pigment loss.CLINICAL FEATURESTotally amelanotic macule (patch) surrounded by normal skinVitiligo macules characteristically have fairly discrete margins and they are round, oval or linear in shapeLesions enlarge centrifugally over time, but the rate may be slow or rapidVitiligo macule patches ranges from millimeter to centimeter in size

CYTOLOGY

Normal skin is pigmented with melanin that is produced by melanocytes

Detection by Masson Silver Stain

Therefore white spots are due to melanocyte deathDISTRIBUTION PATTERN OF VITILIGO

Sub types of Vitiligo Differ by anatomical location, and size of lesions

Focal A few isolated lesions, most common in childrenSegmental unilateral distributionAcrofacial fingers and periorificial areasUniversal almost total depigmentationGeneralized most common, symmetrical distribution, occurs symmetrically on both sides of the bodyMucosal Depigmentation of only the mucous membraneCauses of Vitiligo

HYPOTHESIZED CAUSESAutoimmune theory: Cell mediated immune processBiochemical TheoryOxidative Stress TheoryMelaninMelanin is black pigment of skin, hair & eyesSynthesis occurs in melanosomes present in melanocytes.Tyrosine is the precursor of melanin and tyrosinase is the enzyme involved in its formationMelanochromes formed from tyrosine polymerizes to form melanin polymers

MELANIN SYNTHESISTyrosine

DOPA

Dopamine

Leucodopachrome Cysteine

5,6-Dihydroxyindole Melanin red polymers Indole 5-6-quinone Melanochrome Melanin black polymers

THE PATHOGENESIS OF VITILIGOChemical Melanocytotoxin:

1) Melanin synthesis can be triggered by:Sunburn, skin injury or exposure to cytotoxic compound stimulate melanin synthesisMelanocyte stimulating hormone induced by UV exposureCytokines produced during emotional stress or physical trauma

2) Specific Quinones (Dopa Quinone) and Indoles (Dihydroxy indoles) are generated as intermediates during melanin synthesis

3) Quinones & Indoles, if abundant in the cells, can readily oxidize either enzymatically or spontaneously and produce reactive oxygen species and ultimately induce apoptosis.Apoptosis in Vitiligo Melanocytes1. Exposure of melanocytes to pigment inducers via action of tyrosinase related protein 1 (Tyrp 1) results in generation of intracellular quinone

2. Reactive oxygen species (ROS) forms

3. ROS stimulates the apoptotic pathway

4. Potentially could lead to cell death or interact with endogenous or regulated antioxidants

Essentials of Vitiligo Etiology in DiagramStress to the skin in form of wound, burn, excessive sun exposure or contact with bleching phenol

Differential gene expression among melanocytes

Inflammatory infiltrate of T cells & macrophages

4. Further induce melanocyte apoptosis

TREATMENT SCHEME FOR VITILIGO

Where Depigmentation Therapy Required

Generalized vitiligoTypical appearance of a man with generalized vitiligo affecting the skin around eyes, nose, mouth, and the chest and hands

List of Depigmenting Agents

MONOBENZONEMonobenzyl ether of hydroquinone (MBEH)Chemical Name: P- (Benzyloxy) - PhenolOliver et al. discovered it on 1939Acts as a skin sensitizerTopical application increases the excretion of melanin from melanocytes in animalDepigmentation spreads to distant sites unexposed to Monobenzone, indicating that it induces a progressive systemic reaction against melanocytesMechanism of ActionMany theories have been proposed:

MBEH reacts with tyrosinase, the key enzyme in melanin synthesis, to form a reactive quinone product. This quinone metabolite in turn binds covalently to cysteine residues in tyrosinase proteins through the sulfhydryl (-SH) group to form hapten-carrier complexes, i.e., generation of neo-antigens in the tyrosinase peptide chain occurs which excites a systemic, melanocyte destructive, inflammatory response.

MBEH induces cellular oxidative stress in exposed pigmented cells by producing reactive oxygen species (ROS) such as peroxide. This induces lysosomal degradation of melanosomes by autophagy, in addition to disruption of melanosomal membranes and melanosome structure. This is followed by increased surface expression of melanosomal antigens by both major histocompatibility complex (MHC) class I and II routes and initiation of melanocyte Ag-specific T-cell responses.

Cont.ROS generation also results in release of tyrosinase and MART-1 antigen containing exosomes which further contributes to immune response.

Rapid and persistent innate immune activation also occurs in MBEH-exposed skin. MBEH is a contact-sensitizer inducing a type IV delayed type hypersensitivity response against the quinone hapten mentioned earlier. This depends on the production of pro-inflammatory cytokines such as interleukin (IL)-1b and IL-18 by the Langerhans cells or keratinocytes.

Electron Microscopy Necrotic changes consisting plasma membrane and cytoplasmic disintegration

DNA fragmetation treated skinwithin Monobenzyl Ether of Hydroquinone

Apoptosis is shown inconfocal microscopic images of explant cultures exposed to 5 ml of 250mM MBEH (Monobenzyl Ether of Hydroquinone) for 24 hours.

23Side Effects of MonobenzoneMild burning, irritation, redness, cracking, or peeling of the treated skin may occur. If any of these effects persist or worsen, doctor needs to be informed.

Note: Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue,or throat.

Why Monobenzone????MBEH is the most widely used depigmenting agentMonomethyl ether of Hydroquinine / 4-Methoxy Phenol requires longer time prior to the onset of visible depigmentationApplication of 88% Phenol solution on large areas proved to be toxic to Liver and Kidney. Cardiovascular shock, cardiac arrythmias, bradycardia as well as metabolic acidosis with in 6 hours of skin peeling procedures with phenol. Different type of lasers are selectively destructive to melanocytes but technique is painful and expensive. Moreover these are more efficient in patients with Koebner Phenomenon (skin lesions which appear at the site of injury). Moreover treatment is only available in the clinic. Patients with negetive Koebner may relapse.Cyrotherapyrequires an experienced person hence treatment is hospital based. It gives edema, pain and bulla formation as side effects.Moreover it is suitable for small lesions since single sitting can not be utilized for extensive viiligo.Topical Imatinib, Imiquimod and Diphencyprone may be considered as potential depigmenting agents, but require further investigation

25Efficacy of Monobenzone TherapyResidual patches of vitiligo affecting more than 70% of her skin surfaceDepigmentation after topical application of 20% Monobenzone daily during 8 months

Why Treatment is Important???Although vitiligo is usually not harmful medically and causes no physical pain, its emotional and psychological effects can be devastating. In India, vitiligo patients, especially women, are sometimes discriminated against in marriage. Developing vitiligo after marriage can be grounds for divorce.White patches of vitiligo can affect emotional and psychological well-being and self-esteem. People with vitiligo can experience emotional stress

ConclusionMost commonly acquired Hypomelanosis.Known as Ven kushtam in India, means White Leprosy.Extremly disfiguring, leading to significant patient morbidity.Low self esteem, poor body image and poor quality of life has been found in patients.Depigmentation is the only option when more than 70% of the body covered with vitiligo.Monobenzone induce depigmentation that is clinically and histologically indistinguishable from vitiligo vulgaris.Superiority of Monobenzone comes when it gives a uniform white colorReferencesJG van den Boorn et al. Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG. Plis One 2010;5(5) : 1-12JG van den Boorn et al. Autoimmune Destruction of Skin Melanocytes by Perilesional T Cells from Vitiligo Patients Journal of Investigative Dermatology 2009; 129: 2220-32Thomas J. Childhood Vitiligo An Overview. Journal of the Indian Society of Teledermatology, 2008;2(4) : 1-6Van Geel et al. In vivo vitiligo induction and therapy model: double-blind, randomized clinical trial. Pigment Cell Melanoma Res. 2011;25: 5765Gupta D, Kumari R and Thappa DM. Depigmentation therapies in Vitiligo. Indian Journal of Dermatology, Venereology and Leprology 2012;78(1) : 49-58Draelos ZD. The combination of 2% 4-hydroxyanisole (mequinol) and 0.01% tretinoin effectively improves the appearance of solar lentigines in ethnic groupsAl-Bayati MA. Analysis of causes that led to the development of vitiligo in Jeanetts case with recommendations for clinical tests and treatments. M.A. Al-Bayati/Medical Veritas 2007; 4: 125162Westerhof W. Vitiligo Management Update. Skin Therapy Letter 2000; 6(5): 1-2Schallreuter KU et al. Vitiligo pathogenesis: autoimmune disease, genetic defect, excessive reactive oxygen species, calcium imbalance, or what else? Experimental Dermatology 2008; 17: 13960.Nordlund JJ, Le Poole C, and Boissy RE. Clinical and Basic Immunodermatology 2008, 4, 661-89Hariharan V et. al. Monobenzyl Ether of Hydroquinone and 4-Tertiary Butyl Phenol Activate Markedly Different Physiological Responses in Melanocytes: Relevance to Skin Depigmentation. Journal of Investigative Dermatology 2010; 130:21120.Kavuossi H. Induction of depigmentation in a universal vitiligo patient with combination of cryotherapy and phenol. Journal of Pakistan Association of Dermatologists 2009; 19: 112-4.Shajil EM et al. Vitiligo: pathomechanisms and Genetic Polymorphisms of genes. Indian Journal of Experimental Biology 2006;44:526-39www.clinicalpharmacy.ir/Upload/Modules/Contents/Vitiligo.pdfDepigmenting Agents: Skin-lightening Products for Patients with Facial Melasma. European Dermatology, 2010;5:6873Lotti T et al. New and Experimental Treatments of Vitiligo and Other Hypomelanoses. Dermatol Clin 2007;25 :393400Falabella R and Barona MI. Update on skin repigmentation therapies in vitiligo. Pigment Cell Melanoma Res. 2008;22: 4265Petit L and Pierard GI. Skin Lightening products revisited. International Journal of Cosmetic Science 2003;25:169-81Zanini M. Depigmentation therapy for generalized vitiligo with topical 88% phenol solution. An Bras Dermatol. 2005;80(4):415-6.www.msu.edu/~comptona/Vitiligo/Vitiligo%20Vulgaris.ppt

Remember, A little Consideration, A Little Thought for them makes all the differences. No wonder they are one amongst us. And last, but not the least, Monobenzone- a scientifically established treatment for vitiligo.

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