VITILIGO

DR.SUMIT KUMAR YADAV

SMS MEDICAL COLLEGE JAPIUR
AIIMS DELHI
 INTRODUCTION
• Common depigmenting skin disorder, characterized by acquired,
idiopathic, progressive, circumscribed hypomelanosis of the skin
and hair, with total absence of melanocytes microscopically.

• Vitiligo is a psychologically devastating and frequently recalcitrant

skin disorder.

• Resulting in low self-esteem, poor body image and difficulties in

sexual relationships.
 EPIDEMIOLOGY
• The prevalence of vitiligo is reasonably consistent among different
populations:
• ∼0.38% in Caucasians,
• 0.34% in Afro-Caribbeans,
• 0.46% in Indians,
• Though perhaps somewhat less frequent in Han Chinese, 0.093%.
• Vitiligo affect both genders equally, though women are overrepresented
among patients seeking clinical care.
• Vitiligo can develop at any age, with a mean age-of-onset in Caucasian
patients of about 24 years.
• M/c subtype, generalized vitiligo (GV), is an autoimmune disease that
is associated with other autoimmune diseases in about 20%–30% of
patients.
 ETIOLOGY AND PATHOGENESIS
• The pathogenesis is complex and involves the interplay of multiple
factors; however, the exact pathogenesis is not well known.

• INHERITANCE OF VITILIGO
• The inheritance is polygenic.

• Family history exists in 6.25%-38% of patients with vitiligo.

• Those who have recessive homozygosity at 3 epistatically

interacting autosomal diallelic loci will be affected by vitiligo
• Molecular genetics-based studies
• Autoimmune susceptibility (AIS)-1, -2 (chromosome 7) and
systemic lupus erythematosus vitiligo-related gene (SLEV1)
(chromosome 17) both associated loci for GV and concomitant
autoimmune diseases.

• Methylation was increased and hypermethylation of the

methylation-sensitive region in IL-10 that could alter genes
expression in autoimmunity.

• Role of transforming growth factor beta-receptor Ⅱ(TGFBR2),

which inhibits the inflammatory pathways and lymphocyte
activation was revealed.
• Melanocyte proliferating gene 1 (MYG1),is elevated in skin of both
vitiliginous patients with activity, and without activity.

• Human leukocyte antigen

• HLADRB1* 07, HLA-A2, 11, 28, 31, 33, HLA-B17, 35, 40 and 44.

• Susceptibility loci of vitiligo are on chromosome 6 and in the MHC.

• At 6q27,2 SNPS found with 3 unlinked genes. These gene include

RNASET2, which responsible for ribonuclease (RNAse).
• The other two genes are the chemokine receptor 6 gene (CCR6), and
FGFR10P are imperative to progressing of the cycle of the cell that
produce receptor of (FGF).

• Genes encode discoidin domain receptor 1 (DDR1), and tyrosine

kinase receptor play role in cell’s progression and function, both
were involved in vitiligo.
• THEORIES FOR VITILIGO PATHOGENESIS
• THE NEURAL THEORY

• Early theories: The “neural theory” supposed

• By Lerner’s (1959) was based on the fact that SV follows the course
of the dermatome with exhibiting hyperhidrosis and emotional upset

• The sympathetic nervous system’s role:

• Dysfunction of sympathetic nervous system’s role (SNS) activity
affect melanin production and lead to depigmentation.
• Approximately, the cutaneous blood flow was higher three times on
the lesions vs normal skin in SV.
• Neuropeptide and neuronal markers:
• NPY increased in the marginal areas of lesions in half of the patients
vs normal, and associated with noradrenaline with exerting a local
autonomic effect.
• CGRP was also non-significantly increased in vitiligo.
• Precipitating factor, as, stress, produce significant level of
neuropeptides such as NPY that induct the disease.
• Increased levels of nerve growth factor (NGF) significantly in
vitiligo.
• Stress up regulates NGF expression in hair follicles, decreases the
high affinity TrkA receptor, increases production of p75NTR
NGFreceptor, and increases in dorsal root ganglia the substance P
neurons.
• HVA and VMA levels corresponded to the activity of the disease.

• Stressors result in catecholamines discharge, which bind α-R in the

mucosa and skin arteriolar wall leading to vasoconstriction, hypoxia,
and overproduction of oxygen radicals that destroy melanocytes.

• Mental stress could stimulate the hypothalamic-pituitary-adrenal

axis and then secretion of catecholamines.
• The autoimmune hypothesis
• The etio-pathogenesis of “generalized” or non-segmental vitiligo is
better explained by autoimmune mechanisms as vitiligo often has
autoimmune comorbidities and it often responds to
immunosuppressive treatments.

• The role of humoral immunity:

• TH antibodies revealed significantly in non-SV. Also, in non-SV,
antibodies against MCHR1 (melanin-concentrating hormone
receptor 1), tyrosinase[37] and pigment cellsurface antigens were
noted.
• In 80% of active vitiligo patients, immunoglobulin G (IgG) and
immunoglobulin M (IgM) against melanocytes were found.
• The role of cell-mediated immunity
• T cell had dramatic production of (IL-2R), and increased CD8:CD4
ratio.

• Thus, melanocytes destruction may be cytotoxic CD8 T-cell

mediated.

• Perilesional HLA-DR production (MHC class Ⅱ receptor) exhibited

in all of the patients with vitiligo, especially along suprabasal and
basal keratinocytes, due to local T cell reactivity.

• In addition, macrophages were numerous in vitiligo vs controls,

whereas the CD36 subset of macrophages were higher in the later
• The role of cytokines in vitiligo:
• There are significantly increased expression of
• Tumor necrosis factor-α (TNF-α),
• Interferon-γ (IFN-γ),
• IL-10.
• As IFN-γ and TNF-α are T helper cell-1 (Th1) cytokines, so vitiligo
is mediated by the Th1 response.

• IL-17 plays role with macrophages, keratinocytes, and fibroblasts.

• In addition, it activates the expression of others, as IL-1 and IL-6,

and TNF-α.
• The biochemical Theory-
• Reactive oxygen species model
• Oxidative stress hypothesis suggests that imbalanced redox
(reduction-oxidation) state of the vitiliginous skin.

• This results in the dramatic production of reactive oxygen species

(ROS), as H2O2.

• ROS oxidize components of the cell leading to melanocytes

destruction and creating the depigmented macules.
• The role of tetrahydrobiopterin recycling in vitiligo:
• Another cellular pathway affected by accumulating H2O2 involves
tetrahydrobiopterin.
• Tyrosinase is an imperative enzyme in formation of melanin.
• L-tyrosine synthased from L-phenylalanine by the phenylalanine
hydroxylase (PAH).
• The 5, 6, 7, 8-tetrahydrobiopterin or 6BH4 is essential cofactor for
this process is.
• Defective recycling of 6BH4 lead to excess 7BH4 that is an
inhibitor of PAH.
• Uncoupled PAH and 7BH4 found in suction blister material from
the skin of vitiligo patients.
• There are at least 5 important pathways enrolled in H2O2
overproduction in vitiligo:
• (1) Defective recycling of 6BH4
• (2) Catecholamine formation increased as levels of monoamine
oxidase A (MAO) increased
• (3) Inhibition of thioredoxin/thioredoxin reductase by calcium
• (4) NADPH oxidase activities increased by the cellular infiltrate and
• (5) Nitric oxide synthase (NOS) activities increased
• Oxidative stress affects calcium homeostasis at the cellular level[72]
in melanocytes and keratinocytes in vitiliginous patients.
• Zinc-α2-Glycoprotein deficiency hypothesis
• Pathogenesis of vitiligo could be attributed to decrease in ZAG as
follows:
• (1) ZAG is acting as a keratinocyte-derived factor influencing
melanocyte proliferation and dendricity.
• So, ZAG could be considered as a marker of cells differentiation and
maturation.

• (2) A chronic detachment of melanocytes is an imperative pillar in

the pathogenesis of vitiligo.
• Thus, melanocyte adhesions to the other cells in epidermis will be
impaired in the lack of ZAG.
• (3) Topical steroids are the most safe and effective forms of
treatment for vitiligo, especially for the localized one, because of
their ability to increase ZAG expression.

• (4) Zinc can precipitate ZAG.

• Thus, the effectivity of zinc in treating this disease is related to its
ability to precipitate circulating ZAG at the site of vitiligo.

• (5) The linkage signals on chromosome 7 in patients with GV and

associated autoimmune diseases have been reported.
• Surprisingly, ZAG gene is located on the chromosome 7.
• Viral theory
• There is a strong association between vitiligo and chronic hepatitis
C virus (HCV) infection and autoimmune hepatitis.

• Previous or concurrent cytomegalovirus (CMV) infections may

induce the etio-pathogenesis or deterioration of vitiligo.

• Epstein-Barr virus, hepatitis E virus, herpes virus and the human

immunodeficiency virus (HIV) also have suspicious association
with vitiligo.
• Intrinsic theory
• Melanocytes in vitiligo have an intrinsic defect leading to their
death.
• They demonstrate different abnormalities, including
• Abnormal rough endoplasmic reticulum or
• Deficiency of unidentified melanocyte growth factors such as basic
fibroblast growth factor (bFGF) and
• Decrease in the number of elanocytes expressing the c-kit receptor
in lesional skin.
• Melanocytes require a constant keratinocytederived c-Kit
stimulation for their maintenance,
• Thus weak expression of keratinocyte-derived factors, as stem cell
factor (SCF), may lead to passive melanocyte death and might
explain the Koebner phenomenon.
• Cellular, molecular and biochemical alterations and melanocytes
loss of in vitiligo
• Malfunctioning melanocytes found in vitiliginous lesions.
• Now, 2 pathways have been supposed for melanocytes loss:

• Highly programmed death by apoptosis.

• Accelerated cell senescence.

• Apoptosis and accelerated cell senescence:
• Melanocytes from non-lesional skin of vitiligo patients have
abnormalities as cytoplasm vacuolization, rough endoplasmic
reticulum dilatation, DNA marginalization in the nucleus, loss of
dendrites and detachment.
• keratinocytes, apoptosis occurs at least in the traumatized vitiligo
skin.
• Thus, basal and suprabasal epidermal cells in the depigmented and
normally pigmented skin show degeneration due to swelling of the
membrane-bound organelles, formation of vacuoles and cytoplasm
condensation.
• Vitiligo could inducted by trauma (Koebner’s phenomenon).

• Lee et al revealed the lower expression levels of the antiapoptotic

Bcl-2 and FLIP proteins in vitiliginous skin vs the normally
pigmented skin.

• On the other hand, there was dramatic levels of the proapoptoticBax

and p53 proteins and of the active forms of caspase-3, 8 and 9.

• Apoptosis triggered by normal developmental program, UV light,

H2O2, staurosporine and other stimuli.

• NALP1 gene that stimulates cellular apoptosis, is associated with

vitiligo susceptibility
• low levels of GF asSCF, endothelin-1 (ET-1) or high levels of
melanocyte inhibiting cytokines, as TNF-α and IL-6 may lead to
keratinocyte apoptosis, and then apoptosis of melanocytes.
• Melanocytorrhagy theory:
• Gauthier et al[78] in 2003 mentioned that NSV occurs due to
“melanocytorrhagy”, or a chronic melanocytes detachment and loss
caused by trauma and other stressors include catecholamines, ROS,
or autoimmune elements.

• Impaired cell adhesion plays a role in vitiligo pathogenesis as the

synthesis of extracellular matrix components by keratinocytes may
be defective, the presence of focal gaps in the basement membrane
and impaired formation of basement membrane.

• These abnormalities weaken the basal attachment of melanocytes.

• Trauma could aggravate this susceptibility with subsequent chronic
melanocyte loss, known as melanocytorrhagy.

• Le Poole et al[112] mentioned that the protein tenascin may play a

role in decreasing melanocytes adhesion in vitiligo.

• This protein was highly expressed in patients with vitiligo than the
controls. This can explain the development of vitiligo by Koebner
phenomenon, which represent “transepidermal migration”
• Integrated theory (Conversion theory)

• Despite all the mentioned theories are attractive, it is likely that

vitiligo is a result of the convergence of these pathological
pathways.

• Most experts agree that vitiligo may be a syndrome with a multi-

factorial etiology rather than a single entity.
 CLINICAL MANIFESTATIONS
• Hypomelanotic macules are usually first noted on the sunexposed
areas of skin, on the face or on the dorsa of hands.

• These areas are prone to sunburn.

• Rarely, itching in the absence of sunburn may occur. Damage to the

‘normal’ skin frequently results in an area of depigmentation—an
isomorphic or Koebner phenomenon .

• The amelanotic macules in vitiligo are found particularly in areas

that are normally hyperpigmented, for example the face, axillae,
groins, areolae and genitalia.
• Areas subjected to repeated friction and trauma are also likely to be
affected, for example the dorsa of hands, feet, elbows, knees and
ankles.

• The macules have a convex outline, increase irregularly in size and

fuse with neighbouring lesions to form complex patterns.

• The hairs in the patches frequently remain normally pigmented, but

in older lesions the hairs too are often amelanotic.

• The main symptom is the cosmetic disability, although some

patients present because of sunburn in the amelanotic areas.
• Patients with vitiligo present with one to several amelanotic macules
that appear chalk- or milk-white in color, surrounded by a normal or
a hyperpigmented border.

• Very rarely, the patches may have a red, inflammatory border.

• The lesions are usually well-demarcated, but the margins may be

scalloped.
• Lesions enlarge centrifugally at an unpredictable rate and can appear
on any body site, including mucous membranes.
• However, initial lesions occur most frequently on the hands,
forearms, feet and face.
• The most commonly affected sites are the face, upper part of the
chest, dorsal aspect of the hands, axillae and groin.
• There is a tendency for the skin around orifices to be affected,
namely the eyes, nose, mouth, ears, nipples, umbilicus, penis, vulva
and anus.
• Local loss of pigment may occur around nevi and melanomas, the
so-called halo phenomenon.
• Halo nevi are also common in patients with vitiligo.
• Vitiligo like leukoderma occurs in approximately 1%of melanoma
patients.
• Lesions of vitiligo are hypersensitive to ultraviolet (UV) light and
burn readily when exposed to the sun.
• It is not unusual to note the onset of vitiligo after severe sunburn.
• Although ocular abnormalities are increased in patients with vitiligo,
including iritis and retinal pigmentary abnormalities, patients have
no visual complaints.
CLASSIFICATION
Vitiligo Global Issues Consensus
Conference-2002
 Vitiligo european tasK FORCE
TYPES OF VITILIGO SUBTYPES
NONSEGMENTAL VITILIGO UNIVERSALIS VITILIGO,
GENERALISED VITILIGO,
ACROFACIAL VITILIGO,
MUCOSAL VITILIGO,
FOCAL VITILIGO
SEGMENTAL VITILIGO
MIXED VITILIGO COMBINATION OF INITIAL SV FOLLOWED
BY B/L NSV
• Vitiligo vulgaris—multiple scattered lesions distributed in a more or
less symmetrical pattern.
• The most common presentation of GV.
• Acrofacial:
• It can affect, face, head, hands and feet,
• Preferably involve the perioral region and the extremities of digits
• Universal: is the form that affects the largest extent of tegument (80-
90% of body surface),
• The generalized or common form usually precedes it.
• Most severe form of GV
• Mucosal:
• Affects the oral and genital mucosae.

• Furthermore, areas of mucosa may also be affected in patients with

acrofacial, common, or universal forms;

• When it involves only one mucosal site it is classified as

indeterminate.
• Mixed: it is the concomitant involvement of segmental and non-
segmental vitiligo.

• Most often, the segmental form precedes NSV.

• Focal:
• Isolated white macule without segmental distribution.

• This form can evolve to segmental or NSV forms.

• Follicular vitiligo:
• Form of generalised vitiligo seen in black patient that primary
involve follicular reservoir with limited skin involvement.
• Segmental Vitiligo:
• It can affect one, two or multiple Segments.
• The unisegmental form is the most common one and consists of one
or more white macules on one side of the body, usually respecting
the body midline, and
• There is also involvement of body hair (leukotrichia) besides rapid
onset of the condition.
• Less commonly, it can affect two or more segments and even have
bilateral segmental distribution, starting simultaneously or not.
• Can be blaschoid pattern,checker board pattern, phylloid pattern,
dermatomal pattern
• Facial segmental vitiligo:
• Han et al classified five subtypes:
I. a:lesion initiate from rt side of forehead and courses midline of
face and spread down to eyeblall,nose on lt side
b:forehead and scalp hair
II. Start b/w nose and lip then arches into preauricular area
III. start from lower lip and spreads down to chin and neck
IV. Mid level face from forehead to lower cheek but selectively
appeared on rt side of face not crossing mid line
V. Lesion distributed mostly over right orbital area
 Childhood vitiligo
• Childhood vitiligo deserves special attention.
• frequently (50%), the disease onset is before 20 years of age and, in
25% of the cases, it starts before the age of 10 years.
• The Mean age at onset of childhood vitiligo in an Indian study was
6.2 years
• In general, childhood vitiligo differs from the adult disease in the
following aspects:
• a female preponderance is observed,
• segmental presentation is more common and
• Associated other autoimmune or endocrine disorders are rarer.
• Vitiligo vulgaris is the most common clinical type observed in
various clinical studies,
• followed by focal vitiligo and SV.
• Acrofacial and mucosal vitiligo have a lower incidence in
childhood.
• The rarest type seen during childhood is the universal vitiligo.
• Common initial site of onset of both NSV and SV in children is the
face and neck.
• In NSV, initial lesions are periocular, perinasal or perioral, and
gradually spread to other body parts, in a more or less symmetrical
manner.
• Perineum, perianal area and, in infancy, the diaper area may be the
initial site of occurrence of skin lesions.
• Although extensive areas of depigmentation may be present,
majority of the children have <20% body surface area (BSA)
involvement.
• Koebnerization may be more frequent in childhood vitiligo because
of higher mobility and playfulness in this age group.
• The course of childhood vitiligo is mostly stable or regressive;
• only few patients experience progressive or recurrent disease.
• Complete spontaneous repigmentation of NSV is unusual.
• However, as compared to adults, the rate of spontaneous
repigmentation is more in children, especially in tropical countries
and during summer months.
 RELATED PHYSICAL FINDINGS
• Often associated with a variety of other conditions, principally
autoimmune diseases.
• Most prevalent associated autoimmune disease is autoimmune
thyroid dysfunction, either hypothyroidism (Hashimoto’s
thyroiditis) or hyperthyroidism (Grave’s disease).
• Other autoimmune diseases are
• Rheumatoid arthritis,
• Psoriasis,
• Type 1 diabetes mellitus (usually adult-onset),
• Pernicious anemia,
• systemic lupus erythematosus, and
• Addison’s disease
• Vitiligo can also be part of the Vogt–Koyanagi– Harada (VKH)
syndrome, a multiorgan disorder that affects pigmented
structures, such as the eye, inner ear, meninges, and skin.
• role of cell-mediated immunity in VKH, particularly involving
CD4+ T cells and Th1 cytokines.
• Another very rare multiorgan disorder, Alezzandrini
syndrome, associates facial skin depigmentation, poliosis,
deafness, and unilateral tapetoretinal degeneration of the
eye.
• However, many investigators now believe that VKH and
Alezzandrini’s syndrome are merely different clinical
expressions of the same fundamental disease
• DIAGNOSIS
• The diagnosis of vitiligo is established principally on clinical
grounds, which may include distribution and extent of
lesions, and natural history of disease.
• laboratory tests include
• thyroid-stimulating hormone levels,
• antinuclear antibodies,
• and complete blood count.
• Also consider testing for serum antithyroglobulin and
antithyroid peroxidase antibodies, particularly when patients
have signs and symptoms suggestive of thyroid disease.
 histopathology
• Marked absence of melanocytes and melanin in the epidermis.
• Recent immunohistochemical studies with a large panel of
antibodies show only an occasional melanocyte in lesional skin
• Electron microscopy studies confi rm the loss of melanocytes, which
appear to be replaced by Langerhans’ cells.
• In the epidermis of areas around the margins of vitiligo are
abnormalities of keratinocytes as well as degenerating melanocytes.
• There is increased cellularity of the dermis and occasional colloid
amyloid bodies are found.
• In infl ammatory vitiligo, where there is a raised erythematous
border, there is an infi ltrate of lymphocytes and histiocytes.
• This infi ltrate is also found in the marginal areas of some biopsies.