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N U M B E R 7

INtROdUctIONHaving clear, smooth, evenly colored skin is desired by many; some are fortunate to have it, but most are not. Skin color can be altered by disease or exposure to miscellaneous agents; some patients have a change in pigment coloration as a result of some inflamma-tory disease, including acne or atopic dermatitis.

The skin cells contain melanocytes that produce melanosomes, which are pigment granules contain-ing the complex protein or brown skin-coloring pigment, melanin. The pituitary hormone produces melanocyte stimulating hormone, or MSH, which stimulates melanin production. There are approxi-mately 800 to 1000 melanocytes per square millime-ter of human epidermis; being the same in both light and dark skin individuals but the rate of production of the pigment varies. A number of conditions cause the melanocytes to become either abnormal or ab-normally distributed in the skin.

Most skin conditions that cause discoloration are actually harmless; causing more cosmetic and emo-tional discomfort than medical problems.1,2 Skin hyperpigmentation and photoaging are considered by many to be cosmetically unacceptable and they search for treatment methods to minimize it.

BackgROUNdExposure to such pigments as carotene can result in carotenemia, iron can cause hemodiserin and silver can cause argyria. Other pigmentation problems can be caused by gold used in rheumatoid arthritis treat-ments, tattooing, homogentisic acid in ochronosis and bile pigments.

Changes in skin color may be from hyperpigmenta-tion or hypopigmentation; both can be primary or secondary to other disorders in the body. Table 1 lists common causes of pigmentation disorders.

Primary hyperpigmentation disorders include those that are nevoid, congenital or acquired. Disorders include pigmented nevi, ephelides (juvenile freckles—an inherited characteristic—age spots and café-au-lait spots), and lentigines (solar lentigines, senile len-tigines, senile freckles, liver-spots). Other hyperpig-mentation disorders include arsenical melanosis and those associated with Addison’s disease. Neurofi-bromatosis may produce axillary freckling and café-au-lait spots. A patterned facial hyperpigmentation of the face, usually as a result of estrogen therapy, is melasma, or chloasma; occurring in about 30 to 50% of women taking oral contraceptives.1

SkIN dIScOLORatIONS aNd thEIR tREatMENt

Loyd V. Allen, Jr., Ph.D.

Primary hypopigmentation and depigmentation disorders include vitiligo, albinism and piebaldism. Pigment cells, or melanocytes, are destroyed in viti-ligo, which occurs in aobut 1% of the population and may be associated with hyperthyroidism, hypo-thyroidism, pernicious anemia, diabetes mellitus and Addison’s disease. Albinism is a collection of geneti-cally determined traits. Piebaldism is a localized hy-pomelanosis producing a white forelock. Tuberous sclerosis may produce hypopigmented ash leaf spots and hypopigmented halos can often be seen around nevi and may occur around melanomas.1

Secondary hyperpigmentation disorders include those occurring following a separate dermatologic condition, including acne; it is most commonly seen in dark-skinned individuals and is called postinflam-matory hyperpigmentation. Another disorder is called Berloque hyperpigmentation, which is due to phototoxicity from chemicals in the rinds of limes and other citrus fruits, and to celery. Pigmentation disorders can also be caused by some drugs, includ-ing chloroquine, chlorpromazine, minocycline, and amiodarone. Benzoyl peroxide, fluorouracil and tretinoin can cause hyperpigmentation as well as fixed drug eruptions resulting from phenolphtha-lein in laxatives, trimethoprim-sulfamethoxazole, NSAIDs and tetracyclines.1

Secondary hypopigmentation, or leukoderma may result as a complication due to atopic dermatitis,

taBLE 1: caUSES Of gENERaLIzEd hypERpIgMENtatION.Congenital • Familial • RacialUltraviolet light irradiationEndocrine disorders • Acromegaly • Chronic primary hypoadrenalism • Cushing’s syndrome with high ACTH • Estrogens • PregnancySystemic Disease • Biliary cirrhosis, primary • Chronic renal failure • Cachexia (Tuberculosis, Malignancy) • Hemochromatosis • Malabsorption (Whipples disease, Celiac disease)Drug Induced (See table 2)

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RxTriad-A publication of the International Journal of Pharmaceutical Compounding. © 2007 IJPC. All rights reserved.

lichen planus, psoriasis, discoid lupus erythrematosus and lichen simplex chronicus. Liquid nitrogen used on patients with olive or darker complexions may result in hy-popigmentation or depigmentation. High concentrations of corticosteroid injected intralesionally or intra-articularly may also cause localized temporary hypopigmen-tation.1

taBLE 2: agENtS OR dRUgS that caN caUSE SkIN hypERpIgMENtatION.AmiodaroneArsenicBenzoyl peroxideBleomycinBusulfanChloroquineChlorpromazineCyclophosphamideEstrogensFluorouracilHeavy metal poisoningHydroxychloroquineIronMinocyclineNicotinic acid (Niacin)Nonsteroidal anti-inflammatory agents (NSAIDs)PhenolphthaleinPhenothiazinesPhenytoinSteroidsTetracyclineTretinoinTrimethoprim-Sulfamethoxazole

SyMptOMSQuestions for the medical history of the patient can involve family (Does anyone else in your family have a similar problem?), timing (When did the discoloration begin? Was it sudden? Is it getting worse, and if so, how quickly), quality (Describe the change. Is the skin getting darker or lighter?), location (Where is the discoloration? Is there a pattern to it?), aggravating factors (What medications are you using? Are you often exposed to the sun or a sun lamp? What is your diet?) and miscellaneous questions involving other symptoms they might have as well as any rashes or skin lesions.

A trained dermatologist can generally recognize the pattern of discoloration immediately and name and characterize the discoloration. Some of these pigment changes reflect internal diseases that must be identi-fied and treated.

Table 3 lists some symptoms, diseases and causative factors related to hyperpigmentation disorders.

Some body chemicals, such as bilirubin, can be deposited in the skin and cause a discoloration. Heavy metals, such as silver, gold and iron each have a characteristic color when they can be seen within the skin. Table 2 lists a number of these agents as well as some drugs that can cause pigmentation disorders.

taBLE 3: SyMptOMS Of aNd dISORdERS RELatEd tO hypERpIgMENtatION.Acanthosis nigricansActinic keratosis-sometimes causing a red-brown skinBiliary cirrhosisBirthmarks (Nevus)BruiseBlue skinCafé-au-lait spotsChloasmaDry gangreneErythema abigne—a red brown discoloration resulting from heat exposureFamilial polyposis; results in a darkening of the gumsFrecklesFrostbiteHemochromatosis (Bronze diabetes)JaundiceKaposi’s sarcoma-purple spotsMalignant melanomaMcCune-Albright Syndrome-increased pigmentation, “café au lait” spotsMolesMongolian blue spotNecrotizing fasciitis-violet skinNeurofibromatosis, or von Recklinghausen’s diseasesPeutz-Jeghers syndrome (peri-oral pigmentation)Polycystic ovary syndrome-thickened darkened skin patchesPorphyria cutanea tardaPort wine stainsPregnancy: “Mask of pregnancy”, darkening of the cheeks and forehead; also, darkening of the nipples, genitals and a line down the central abdomen, linea nigra.Purple skinSarcoidosis-purple skin patchesSclerodermaSeborrheic wartSenile wartSun sensitivityUremia-sallow complexionVaricose veinsVenous ulceration from long-term varicose veinsVisceral leishmaniasis

tREatMENtThis article will only address hyper-pigmentation treatment. The goal of therapy in hyperpigmentation disor-ders is to lighten the skin so it blends into the normal skin in the area. Most products (See Table 4) used to lighten the skin contain hydroquinone. Other drugs commonly used in the treatment of hyperpigmentation disorders include azelaic acid, glycolic acid, hydrocorti-sone, kojic acid, tretinoin and triamcin-olone. These are listed in Table 4 and antioxidants and adjuvants used in their formulations are listed in Table 5. Nor-mally, these agents are somewhat irri-tating to sensitive skin. Treatments may take three to six months to produce im-provement. Laser treatments are also available. For treatment of freckles, age spots and other discolorations, using a sunscreen with a sun protection factor (SPF) of at least 15 is a must.

REfERENcES1. Berger TG. Skin, Hair, & Nails.

In: Tierney LM Jr, McPhee SJ, Pa-padakis MA, eds. Current Medical Diagnosis & Treatment. New York: Lange Medical Books/McGraw-Hill; 2003: 138-140.

2. Esterly JS, West LE, West DP. Skin Hyperpigmentation and Photoag-ing. In: Berardi RR, ed. Handbook of Nonprescription Drugs. 14th ed. Washington, DC: American Pharmaceutical Association; 2004: 955-967.

taBLE 5: ExaMpLE aNtIOxIdaNtS aNd adjUVaNtS USEd IN hydROqUINONE pREpaRatIONS.*agENt cONcENtRatION RaNgEOil Soluble Ascorbyl palmitate 0.01-0.5% Butylated hydroxyanisole 0.005-0.02% Butylated hydroxytoluene 0.005-0.02% Lecithin - -Lipoic acid - Tocopherols ( , Δ, ) 0.05-0.5%Water Soluble Ascorbic acid 0.01-0.5% Potassium metabisulfite 0.05-1% Sodium bisulfite 0.05-1% Sodium metabisulfite 0.01-1% Sodium sulfite 0.01-0.2%Adjuvants Ascorbic acid 0.02-0.1% Citric acid 0.005-0.01% EDTA and salts 0.02-0.1% Tartaric acid 0.01-0.02%*See IJPC 3(1); 1999: 52-55.

ExaMpLE fORMULatIONS

Rx Hydroquinone 5% in Isopropyl Alcohol

Rx Hydroquinone 5% Topical Gel

Rx Hydroquinone 5% Topical Stick- Water Repellant

Rx Hydroquinone 5% Topical Stick- Water Soluble

Rx Dexamethasone 0.1%, Hydroquinone 5% and Retinoic Acid 0.1% Ointment

Rx Hydroquinone 5%, Retinoic Acid 0.1% and Triamcinolone 0.1% Gel

Rx Hydroquinone 5%, Retinoic Acid 0.1% and Triamcinolone 0.1% Cream

Rx Hydroquinone 5%, Retinoic Acid 0.1% and Triamcinolone 0.1% Ointment

Rx Hydrocortisone 1%, Hydroquinone 5% and Glycolic Acid 5% Lotion

Rx Hydroquinone 5% Cream

taBLE 4: actIVE INgREdIENtS USEd IN thE tREatMENt Of SkIN hypERpIgMENtatION.Ingredient % UsedAzelaic acid 5-20Glycolic acid 1-20Hydroquinone 1-15Hydrocortisone 0.5-1Kojic acid 2-10Tretinoin 0.025-0.05Triamcinolone 0.025-0.5

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