Transcript 9-Pigmentation disor..

Pigmentation Disorders
Pigmentation Disorders, Introduction
 Normal skin color is composed of a mixture of four biochromes (biological pigments):
1. reduced hemoglobin (blue)
3. carotenoids (yellow; exogenous from diet)
2. oxyhemoglobin (red)
4. melanin (brown)
 The color of skin is principally genetically determined and is largely the result of the
insoluble polymeric pigment melanin produced by melanocytes in a highly
specialized organelle known as the melanosome
 Melanin is the dark pigment that gives skin its color and protects against UV radiation
 Melanocytes synthesize two chemically distinct groups of melanin:
I. nitrogenous eumelanins (black to brown)
II. sulfur-containing pheomelanins (yellow to reddish-brown)
 The type and amount of melanin and its distribution pattern in the surrounding
keratinocytes determine the actual color of the skin, and provide the basis of the
three principal human skin colors: black, brown and white
 These three basic skin colors are genetically determined and are called constitutive
melanin pigmentation
 The normal basic skin color pigmentation can be increased deliberately by exposure to
UVR or pituitary hormones, and this is called inducible melanin pigmentation
 The combination of the constitutive and inducible melanin pigmentation determines what is
called the skin phototype (SPT)
Melanocyte, Melanosome and Keratinocyte
 The melanocyte (pigment cell) resides in the basal layer of the surface layer
of the skin “ epidermis” and supplies melanin (packaged within
melanosomes) to surrounding keratinocytes. Following exposure to UV
light, there is an increase in the number of melanosomes, their melanin
content and their transfer to keratinocytes
Mechanism of pigment formation
UV
Epidermis
Melanocyte
Tyrosine
Tyrosinase
Melanin
Biosynthesis of Pheomelanin & Eumelanin
Melanocyte-stimulating
Melanocyte
hormone
MSH +
Tyrosinase
Dopa (
)
Tyrosinase
Dopachrome tautomerase
Tyrosinase
Modified from Lamoreux et al. Genetics 119: 967-984 August, 1986
Pigmentation Disorders, Introduction, contd.
 Increase of melanin in the epidermis results in a state known as hypermelanosis
(hyperpigmentation), which reflects one of two types of changes:
I. An increase in the number of melanocytes in the epidermis producing increased levels of
melanin, which is called melanocytotic hypermelanosis (an example is lentigo)
II. No increase of melanocytes but an increase in the production of melanin only, which is
called melanotic hypermelanosis (an example is melasma; also known as chloasma)
 Hypermelanosis of both types can result from three factors: genetic; hormonal (as in
Addison disease, when it is caused by an increase in circulating ACTH) and UVR (as in
tanning)
α- MSH (α-melanocortin) & ACTH are produced from a common precursor, proopiomelanocortin.
ACTH also enhances melanogenesis as it shares some structural similarity with a-MSH
 Hypomelanosis (depigmentation) is a decrease of melanin in the epidermis. This
reflects mainly two types of changes:
I. No decrease of melanocytes but a decrease of the production of melanin only that is called
melanopenic hypomelanosis (an example is albinism which is a congenital disease)
II. A decrease in the number or absence of melanocytes in the epidermis producing no or
decreased levels of melanin. This is called melanocytopenic hypomelanosis (an example is
vitiligo which is an acquired idiopathic disorder.)
 Hypomelanosis can result from genetic (as in albinism), from autoimmune (as in vitiligo), or
other inflammatory processes (as in postinflammatory leukoderma in psoriasis)
 Depigmentation could also be secondary such as burn and chemicals
Vitiligo
Pigmentation Disorders, Vitiligo
 Vitiligo (white spot disease) is a loss of skin melanocytes
that causes areas of skin depigmentation of varying sizes,
in various parts
 Clinically, It is characterized by totally white macules, which
enlarge and can affect the entire skin
Macule is an area of skin discoloration, without elevation or
depression and, therefore, nonpalpable. It may be of any
color, white or red for example. Macules may be the result of
hyperpigmentation or hypopigmentation
 Depigmentation may involve 1 or 2 spots (focal vitiligo),
entire body segments (segmental vitiligo), or rarely most of
the skin surface (universal vitiligo)
 It most commonly involves:
The face, digits, dorsal hands, elbows, armpits,
Knees, dorsal ankles, inguinal area,
Anogenital area, umbilicus and nipples,
 Hair in vitiliginous areas is usually white
Vitiligo, Symptoms & Signs
• Cosmetic disfigurement, particularly in darker
skinned individuals, is a psychosocial disaster
• White patches of skin
• Whitening or graying of the hair on scalp,
eyelashes, eyebrows or beard
Vitiligo, Etiology
•
The cause is unknown, but the condition may be autoimmune process, in which the
body destroys its own melanocytes, since autoantibodies to melanocytes were
identified & up to 1/3 of patients have evidence of other autoimmune disease (e.g.,
Addison's disease, diabetes mellitus, pernicious anemia & thyroid dysfunction)
 Predisposing factors:
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Heredity
Vitiligo has a genetic background; >30% of affected individuals have
reported vitiligo in a parent, sibling or child
Individuals from families with an increased prevalence of thyroid disease,
diabetes mellitus, and vitiligo appear to be at increased risk for development of
vitiligo
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Physical trauma (where vitiligo appears at the site of trauma; Koebner
phenomenon),
Exposure to chemicals such as phenols
Illness or emotional stress
Skin injury, burns or inflammatory skin disorders
A sunburn reaction may precipitate vitiligo
Vitiligo, Epidemiology, Course & Prognosis
 Vitiligo affects 0.5 to 2% of the population worldwide. Epidemiology is equal in both
sexes and in all races
 Vitiligo is a chronic disease. It is commonly characterized by rapid onset followed by
a period of stability or slow progression
 Up to 30% of patients may report some spontaneous repigmentation in a few areas,
particularly areas that are exposed to the sun
 Rapidly progressive, or "galloping," vitiligo may quickly lead to extensive
depigmentation with a total loss of pigment in skin and hair, but not eyes
 All depigmented areas are prone to severe sunburn and must be protected with
clothing or sunscreen
 Cosmetic disfigurement can be devastating, especially in dark-skinned patients
 The treatment of vitiligo-associated disease (i.e., thyroid disease) has no impact on
the course of vitiligo
Vitiligo
Management of vitiligo
 The approaches to the management of vitiligo are as follows:
I. Sunscreens: They should be used by all patients with vitiligo. Their objectives are:
1. Protection of involved skin from acute sunburn reaction or repeated solar damage to
depigmented skin
2. Limitation of tanning of normally pigmented skin, especially in fairer-skinned patients
 Active ingredients of sunscreens include chemical agents that absorb incident solar
radiation in the UVB and/or UVA ranges (e.g., PABA, avobenzone & oxybenzone)
and physical agents (e.g., titanium dioxide & zinc oxide) that contain particulate
materials that can block or reflect incident energy and reduce its transmission to skin
 The major measurement of sunscreen photoprotection is the sun protection factor
(SPF): the ratio of the minimal dose of incident sunlight that will produce erythema or
redness (sunburn) on skin with the sunscreen in place (protected) and the dose that
evokes the same reaction on skin without the sunscreen (unprotected)
 Except for total sun avoidance, sunscreens are the best single method of protection
from UV-induced damage to the skin
 Sunscreens with a SPF>30 are reasonable choices to prevent sunburn for most
vitiligo patients and to limit the tanning reaction in fairer-skinned individuals. While all
skin phototypes (SPTs) have a need for sun protection, sunscreens alone are often
adequate management for those vitiligo patients with SPTs I, II and sometimes III
 Vitiligo also can be managed by the use of a cosmetic cover-up solution
II. Repigmentation
 The objective of repigmentation is the permanent return of normal melanin pigmentation.
This may be achieved for local macules with 1-topical glucocorticoids or2- topical
psoralens and UVA and for widespread macules with oral psoralens and UVA (PUVA):
1. Topical glucocorticoids
 Glucocorticoids are prescribed frequently for their immunosuppressive and antiinflammatory properties. They are administered locally, through topical and
intralesional routes. They are prescribed for patients with small patches of vitiligo
 Mechanisms of action includes apoptosis of lymphocytes, inhibitory effects on the
arachidonic acid “AA” cascade (via inhibition of phospholipase A2  inhibition of AA
synthesis) & depression of production of many inflammatory cytokines.
 Initial treatment with intermittent (4 weeks on, 2 weeks off) topical class I
glucocorticoid ointments is practical, simple, and safe for single or a few macules. If
there is no response in 2 months, it is unlikely to be effective
Potent topical corticosteroids can cause hypopigmentation or atrophy in normal
surrounding skin
Side effects occur in areas where the skin is thin, such as on the face and armpits
In general, only nonfluorinated glucocorticoids should be used on armpits and on the
face (perioral dermatitis can develop after the use of fluorinated compounds, e.g.,
diflorasone, on the face)
Glucocorticoid creams are not as effective as psoralen photochemotherapy
2. Topical photochemotherapy
 Phototherapy and photochemotherapy are treatment methods in which UV or visible
radiation is used to induce a therapeutic response either alone or in the presence of
a photosensitizing drug
 It employs topical 8-methoxypsoralen (8-MOP; a photoreactive chemical ) and UVA
(320–400 nm). This procedure should be undertaken for small macules only by
experienced physicians
 Mechanism of action of PUVA: The UV radiation promotes overproduction of MSH
which binds to the melanocortin receptor 1, and stimulates melanocyte proliferation
and induces the activation of tyrosinase, the rate-limiting enzyme in the melanin
pathway  skin pigmentation
 Psoralens must be photoactivated by UVA to produce a beneficial effect. Psoralens
intercalate with DNA and, with subsequent UVA irradiation, cyclobutane adducts are
formed with pyrimidine bases. DNA adducts are formed, causing interstrand crosslinks. These DNA photoproducts may inhibit DNA synthesis  decrease in DNAdependent proliferation  suppression of infiltrating lymphocytes
 PUVA also alters cytokine profiles and cause immunocyte apoptosis, thereby
interrupting immunopathologic processes. In addition, PUVA augments transfer of
melanosomes from melanocytes to keratinocytes because of the UVA
2. Topical photochemotherapy, contd.
 The patient is given “psoralen” (topically for small, scattered patches less than
20% or orally for extensive vitiligo more than 20%)
 Patients treated with these modalities should be monitored for concomitant use
of other potential photosensitizing medications, e.g. benzodiazepines, NSAIDs,
thiazides, sulfonamides and sulfonylureas, before initiation of therapy
 Side effects of PUVA
Nausea, itching, blistering and painful erythema
Hyperpigmentation of the treated patches or the normal skin surrounding
the vitiligo patches
Accelerated skin ageing and increased risk of skin cancer with long-term
exposure to the drug
3. Topical calcineurin inhibitors (Topical immuno-modulators)
 The calcineurin inhibitor tacrolimus is a potent macrolide immunosuppressant
traditionally used to prevent kidney, liver and heart allograft rejection
 Tacrolimus ointment is effective in people with small areas of vitiligo, especially on the
face and neck
 It is effective in repigmenting vitiligo but only in sun-exposed areas. It is reported to
be most effective when combined with UVB
 Calcineurin is a phosphatase that normally dephosphorylates the cytoplasmic subunit
of nuclear factor of activated T cells (NFAT), thus permitting NFAT to translocate to
the nucleus and augment transcription of numerous cytokines
 Tacrolimus works by inhibiting the phosphatase activity of calcineurin, thereby
inhibiting early activation of T-lymphocytes and the production of pro-inflammatory
cytokines, with subsequent suppression of humoral and cell-mediated immune
responses
 A major benefit of topical tacrolimus compared with topical glucocorticoids is that
tacrolimus does not cause skin atrophy and therefore can be used safely in locations
such as the face
 It is well-tolerated when used for extended periods
There is concern that this may be associated with an increased risk of skin
cancer
4. Systemic photochemotherapy
 For more widespread vitiligo, oral PUVA is more practical. Oral PUVA may be done
using sunlight (in summer or in areas with year-round sunlight) and 5-MOP or with
artificial UVA and either 5-MOP or 8-MOP (methoxypsoralen)
5. Narrow-band UVB, 311 nm
 This is just as effective as PUVA and does not require psoralens. It is the treatment
of choice in children <6 years of age
III. Minigrafting
 Minigrafting (transplantation of cultured autologous melanocytes) may be a useful
technique for refractory and stable segmental vitiligo macules
 PUVA may be required after the procedure to unify the color between the graft sites
IV. Depigmentation
 The objective of depigmentation is "one" skin color in patients with extensive vitiligo or
in those who have failed PUVA, who cannot use PUVA, or who reject the PUVA option
 Bleaching of normally pigmented skin with monobenzylether of hydroquinone 20%
(MEH) cream is a permanent, irreversible process (see details later, in melasma)
 The success rate is >90%. The end-stage color of depigmentation with MEH is chalkwhite, as in vitiligo macules
 All those who have bleached are at risk for sunburn from acute solar irradiation