1. Pharmacology-4 PHL 425 First Lecture By Abdelkader Ashour, Ph.D. Phone: 4677212Email: aeashour@ksu.edu.sa

2. Pigmentation Disorders, Introduction  Normal skin color is composed of a mixture of four biochromes (biological pigments): 1.reduced hemoglobin (blue) 2. oxyhemoglobin (red) 3.carotenoids (yellow; exogenous from diet) 4. melanin (brown)  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)  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  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

3.  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 Melanocyte, Melanosome and Keratinocyte

4. Tyrosinase Mechanism of pigment formation Epidermis Melanocyte Tyrosine Melanin UV

5. Modified from Lamoreux et al. Genetics 119: 967-984 August, 1986 Tyrosinase Dopa ( ) Dopachrome tautomerase Tyrosinase Biosynthesis of Pheomelanin & Eumelanin Melanocyte MSH+

6. 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  -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

8. Vitiligo

9. 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

10.  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, Symptoms & Signs

11.  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) Vitiligo, Etiology  Predisposing factors:  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  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

12. Vitiligo, Epidemiology, Course & Prognosis  Vitiligo affects 0.5 to 2% of the population worldwide. Epidemiology is equal in both sexes and in all races  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 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