J Pharm Sci Bioscientific Res. 2020. 10 (1):142-148 ISSN NO. 2271-3681

Review on Skin : Etiology, Diagnosis and Treatment

Sohan A. Patel*1, Jayant. B. Dave2, Timir Y. Mehta3

1. Assistant Professor, Department of Pharmacology, Smt. S M. Shah Pharmacy College, Amasaran, Mahedavad- Ahmedabad, Highway, Gujarat, India 2. Professor, Department of Quality Assurance, L. M. College of Pharmacy, Ahmedabad, Gujarat, India 3. Dermatologist, Samarpan Medical Research Organization, Modasa, Gujarat, India

Article History: ABSTRACT:

Received 29 April 2020 Hyperpigmentation is common dermatological condition. Skin color is determined Accepted 03 May 2020 Available online 11 May 2020 by and other chromophores and is influenced by physical factors (ultraviolet radiation) and other endocrine, autocrine, and paracrine factors. Being Citation: the largest organ of the body, any abnormality in skin color can have impact on the Patel S. A., Dave J. B., Mehta T. Y., Review patients’ psychosocial impairment of life. In Indian population have verities of on Skin Hyperpigmentation: Etiology, Diagnosis and Treatment. J Pharm Sci hyperpigmentation condition on skin due to multifactorial region; hence, a Bioscientific Res. 2020. 10(1):142-148 multipronged approach is needed in such cases. The biggest challenge in such cases is to treat the hyperpigmentation itself; hence, counseling and general treatment *For Correspondence: (the use of broad-spectrum sunscreen, the avoidance of sun exposure, etc.) play Mr. Sohan A. Patel crucial role, and an interdisciplinary approach may be required, especially when Assistant professor, Department of the hyperpigmentation is due to a systemic cause. A thorough understanding of Pharmacology, Smt. S. M. Pharmacy the aetiology and management strategies of hyperpigmentation is of importance College, Amasaran, Bhumapura in caring for those afflicted and also in the development of new therapies. Mahedavad- Ahmedabad, Highway, Gujarat, India. KEY WORDS: Transdermal Drug delivery, Microneedle, Solid microneedle, Hydrogel micro needle. (www.jpsbr.org)

INTRODUCTION corneum cells. Melanin production and skin colour are affected not only by keratinocytes5 figure 1. Hyperpigmentation is a common dermatologic condition among patients of all skin types. Pigmentation disorders are the third most common among dermatologic disorders and cause significant psychosocial impairment.1 Hyperpigmentation of the skin is a common complaint in populations. The majority of the world's population is brown-skinned.2 Variability of constitutive pigmentation around the world is well-established, with some skin tones, especially in Asian and Indian subjects. This review mostly focuses on the skin pigmentation and its variation, as well as associated pigmentary disorders among the Indian population.3 There is great diversity in the color of human Figure 1: A and production of Melanosomes skin across the globe. 4 CAUSES Pigment formation is highly complex. Melanocytes in There are numerous causes of hyperpigmentation. and it cooperation with enzyme tyrosinase are responsible for can be classified in many ways. An etiological classification the production and conversion of dopa to melanin; would simplify the approach to such cases. melanosomes containing pigment are ingested by the keratinocytes, and the melanin is shed with the stratum

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Table 1: Etiological classification of Hyperpigmentation 6 (xii) Imatinib (xiii) Oral contraceptive pills (A) (i) Addison’s disease (I) Deposits – exogenous ochronosis Endocrinologic (ii) Cushing’s syndrome (J) Autoimmune systemic sclerosis (iii) Nelson syndrome (K) Infections (i) Onchocerciasis (iv) Pheochromocytoma (ii)HIV-associated (v) Carcinoid hyperpigmentation (vi) Acromegaly (L) Miscellaneous (i) Tanning vii. Hyperthyroidism (ii) pigmentosus (LPP) viii. (iii) Ashy gray dermatosis (ix) Diabetes (iv) Carbon baby syndrome (B) Nutritional (i) Kwashiorko (v) Bronze baby syndrome (ii) Vitamin B12 deficiency (vi) Extensive Mongolian spots (iii) Folic acid deficiency (vii) Giant melanocytic nevus (iv) Niacin deficiency (viii) Adrenoleukodystrophy (v) Tryptophan deficiency (ix)Familial progressive (vi) Vitamin A deficiency hyperpigmentation (C) Metabolic (i) Porphyria cutanea tarda (PCT) (x) Generalized fixed drug rash (ii) Hemochromatosis (xi)Postinflammatory (iii) Gaucher’s disease hyperpigmentation following (iv) Niemann–Pick disease pemphigus (v) Wilson’s disease or erythroderma (vi) Chronic renal failure (CRF) (xii) Idiopathic eruptive macular (D) Tumoral (i) Mycosis fungoides pigmentation (IEMP) (E) Physical (i) Ultraviolet radiation (xiii) POEMS syndrome (ii) Ionizing radiation (xiv) Cronkhite–Canada syndrome (iii) Thermal radiation (xv) Dyschromatosis universalis (iv) Trauma hereditaria (F) Occupational (i) Ultraviolet radiation (xvi) Reticulate acropigmentation of (ii) Ionizing radiation Kitamura (iii) Thermal radiation (iv) Trauma COMMON HYPERPIGMENTARY DISORDERS (G) Occupational (i) Pigmented contact dermatitis This section includes studies carried out on the variation of (ii) Metal deposition in skin – silver, Indian skin tones across various geographical locations and mercury, gold, bismuth, chromates, their susceptibility to common Hyper-pigmentation copper, and cadmium disorders. In this study, I focus on hyper-pigmentary (iii) Chemical exposure – arsenic and disorders such as, important hyper pigmentary disorders in aromatic hydrocarbons India, namely, , post inflammatory (H) Medications (i) Clofazimine hyperpigmentation (acne, psoriasis, atopic and contact (ii) Amiodarone dermatitis, lichen planus, trauma, drugs, and fixed-drug (iii) Minocycline eruptions), periorbital hyperpigmentation, generalized (iv) Zidovudine hyperpigmentation, Gingival pigmentation, Solar (v) Antimalarial lentigines, Ephelides (), Café-au-lait, macules, Nevi, (vi) Bleomycin Melanoma and precursors7,8,9,10,11,12. (vii) Doxorubicin FEATURES OF HYPERPIGMENTATION (viii) Chlorpromazine Clinical examination (xi) Cyclophosphamide After taking history, the patient has to be examined. First, (x) EGFR inhibitor a general examination of the patient has to be performed (xi) Psoralens to assess the general health of the patient.

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A. General examination syndrome, pheochromocytoma, carcinoid syndrome, and Altered mental status and clubbing is found in patients with hyperthyroidism. However, bradycardia is a feature of Wilson’s disease. Pallor is a feature in those with chronic Addison’s disease. Hypertension is a vital pointer toward renal failure (CRF), Gaucher’s disease, and Niemann–Pick Cushing’s syndrome, pheochromocytoma, CRF, systemic disease, whereas icterus accompanies Wilson’s disease and sclerosis, etc.13 hemochromatosis. Pedal edema is an important finding in B. Cutaneous examination patients with CRF, kwashiorkor, POEMS, and 1. Examination of skin: Different skin condition have hyperthyroidism. Pulse rate often gives important clues for different features Table 2. diagnosis. Tachycardia is found in those with Cushing’s

Table 2: Distinguishing features of Different types of Hyperpigmentation disorders Diseases Distinguishing features Post-inflammatory History or presence of inflammation with erythema and/or scaling and Epidermal hyperpigmentation14 hypermelanosis will appear tan, brown, or dark brown and may take months to years to resolve without treatment. Maturational dyschromia15 Darkening of malar cheeks and forehead in mature richly pigmented skin. polygonal- shaped dark brown to black-colored macular pigmentation over the zygomatic areas of the face. The lesion had ill-defined borders and a rough surface. Periorbital to detect involvement of the upper or lower or both eyelids and extension beyond the hyperpigmentation16 periorbital region, color of hyperpigmented areas (light brown/dark brown/red/blue). Riehl melanosis17 occurs on the face and neck and is characterized by the rapid onset of gray-brown reticular pigmentation. Typically preceded by mild erythema and pruritus, followed by a diffuse‐to‐reticulated hyperpigmentation. Melasma18 Melasma is characterized by brownish macules with irregular contours and clear limits. It appears in sun-exposed areas, especially the face and cervical region, and, less commonly, in the arms and sternal region. Exogenous ochronosis19 Cutaneous disorder characterized by banana‐shaped, yellow‐brown deposits in the dermis and blue-black hue in the skin due to the deposition of small ochre-colored pigment in the dermis secondary to prolonged skin lightening agents or unprotected sun exposure. Acanthosis nigricans20 Acanthosis nigricans is characterized by dark, coarse, thickened skin with a velvety texture. The earliest change is grey-brown/black pigmentation with dryness and roughness that is palpably thickened and covered by small papillomatous elevations, giving it a velvety texture. As thickening increases, skin lines are further accentuated and the surface becomes mammilated and rugose, with the development of larger warty excrescence and Symmetric, hyperpigmented, velvety plaques on the neck and axillae. Dermatosis papulosa The lesions of DPN initially present in adolescent patients as minute, round, skin-colored nigra21 to dark brown macules, resembling freckles, gradually becoming papular and increasing in size and number with age. Nevus of Ota22 Extraoral examination revealed the presence of an asymptomatic blue-grey lesion on the face that had been Onset in infancy or puberty. The discoloration gradually progressed to involve the forehead, temple, malar, periorbital area, sclera, lower palpebral, and ala of the nose and with interspersed pinpoint -like spots. Hori naevus23 Asians, primarily Chinese and Japanese, women aged 20–70 years. The malar region was the most frequently affected area. Blue‐grey to grey‐brown macules primarily on the zygomatic area and less often on the forehead, temples, upper eyelids, and root and alae of the nose. Ephelides24 Red to light brown skin color and 1–3‐mm well‐demarcated hyperpigmented macules that are round, oval or irregular in shape. Areas affected like, Face, neck, chest, arms.

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Lentigines24,25 Lentigines are characterized by their small size (< 0.5 cm), irregular borders, and discrete markings of different shades of brown and black. Area affected like, Sun‐exposed skin, face, hands, forearms, chest back and shins. Lichen planus Lichen planus pigmentosus (LPP) is a condition characterized by persistent and pigmentosus26 asymptomatic slaty-gray pigmentation, predominantly in the face. Oval or irregularly shaped grey‐brown to brown macules and patches in sun‐exposed areas. Erythema dyschromicum A physical examination revealed brownish-grey to greyish-black pigmented macules and perstans27 patches on the trunk and extremities. Inflammatory phase with rim of erythema. Distribution also includes non-sun exposed areas. Actinic lichen planus28 The eruption was distributed over sun-exposed areas, with particular predilection for the face. In most cases the lesions consisted of erythematous brownish plaques with an annular configuration. Erythromelanosis symmetrical patches of reddish‐brown pigmentation with tiny and follicular papules that follicularis faciei et colli29 begin on preauricular areas and cheeks and gradually spread to the submandibular areas. there was diffuse dark‐brown reticulated pigmentation and Well‐demarcated erythema. Post‐chikungunya Small macules of brown‐black pigmentation or slate‐like pigmentation of the pigmentation30 centrofacial area. History of fever, morbilliform skin eruption and polyarthritis.

2. Examination of the nails: All the finger-nails and important findings that help us associate them with the toe nails were diffusely pigmented without discrete band dermatological lesions, for example, hyperpigmentation appearance. Blackish discoloration spread onto the induced by Grave's disease33, vitamin B12 deficiency34, proximal nail folds from all the nails. No pitting or any hepatomegaly is a feature of hemochromatosis35. history of any inflammation or injury to the nail was Treatment Options for Hypepigmentation recognized.31 Treatment is mostly cause specific, but some general 3. Examination of the oral mucosa: The color of measures such as photoprotection (avoidance of sun physiological pigmentation can range from light brown to exposure and the use of broad-spectrum sunscreens) and almost black. They may greatly vary in color as blue, purple, the avoidance of known triggers always help. Counseling is brown, gray or black depending on the quantity and site of an integral part of the therapy, because many conditions melanin in the tissues. 32 are difficult to cure. The management of some the diseases C. Systemic examination has been summarized in Table 3. Systemic examination is more important for diagnosis of hyperpigmentation in many cases, we may come across Table 3: Treatment of conditions causing hyperpigmentation36,37,38,39 Diseases Treatment Photoprotection Lichen planus pigmentosus Topical: steroid, tacrolimus Systemic: steroid, vitamin A, dapsone, colchicine, and hydroxychloroquine Post-inflammatory Skin‐lightening agents, chemical peeling agents and laser hyperpigmentation Maturational dyschromia Skin‐lightening agents, antioxidants, sunscreen, microdermabrasion or chemical peels Periorbital Skin‐lightening agents, chemical peels, IPL, Q‐switched ruby laser, autologous fat hyperpigmentation transplantation, combinations of fat grafting and blepharoplasties, fillers Riehl Complete avoidance of the suspected allergen and allergen‐free soaps and cosmetics Sun‐protective measures, skin‐lightening agents and chemical peels Melasma Combination approach with strict sun protection, cosmetic camouflage, skin‐lightening agents, chemical peels and laser therapy Exogenous ochronosis Dermabrasion, CO2 laser, glycolic acid peelings and Q‐switched laser

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Photoprotection Avoiding alcohol, hepatotoxic drugs, estrogen Porphyria cutanea tarda therapy, and excess iron supplements Phlebotomy Low-dose antimalarials Iron chelating agents Avoidance of products containing tyrosine and phenylalanine Alkaptonuria High doses of vitamin C Nonsteroidal anti-inflammatory drugs Physiotherapy Addison’s disease Replacement of mineralocorticoids and glucocorticoids Surgery of pituitary adenomas Somatostatin analogues Acromegaly Dopamine analogues Growth hormone receptor antagonist (pegvisomant) Vitamin B12 deficiency Intramuscular B12 1mg per week for 1 month followed by 1mg per month till reversal Pellagra Oral nicotinamide 100 mg thrice daily till reversal Weight reduction Topical: retinoids, calcipotriol, and ammonium lactate Systemic: retinoid, metformin, rosiglitazone, and glimepiride Acanthosis nigricans Trichloroacetic peels Long-pulsed alexandrite lasers Keratolytics, skin‐lightening agents, calcipotriol, urea and salicylic acid Dermatosis papulosa nigra Snip excision, curettage, electrodesiccation, light cryotherapy and laser destruction Naevus of Ota Q‐switched ruby, alexandrite and Nd:YAG lasers Avoidance of the causative agents Q-switched frequency doubled Nd–Yag laser Hori naevi Q‐switched ruby, alexandrite and Nd:YAG lasers, cryotherapy Ephelides Sun‐protective measures, skin‐lightening agents, cryotherapy and laser surgery Gaucher’s disease Enzyme replacement therapy with recombinant acid β-glucosidase Substrate reduction therapy (SRT) with eliglustat Systemic sclerosis Topical: steroid, calcipotriol, and retinoid Lentigines Sun‐protective measures, skin‐lightening agents, cryotherapy and laser surgery Erythema dyschromicum Oral corticosteroids, antibiotics (e.g. doxycycline), antimalarials, isoniazid, griseofulvin perstans and UV light therapy have produced variable results Successful treatment with dapsone and clofazimine has been reported in small series Actinic lichen planus Topical and intralesional corticosteroids, antimalarials (e.g. hydroxychloroquine), acitretin and ciclosporin Pigmented contact Avoidance of the allergen dermatitis Topical: steroid, hydroquinone, and tretinoin Glycolic acid peels Erythromelanosis Topical and systemic retinoids, hydroquinone follicularis faciei et colli

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Post‐chikungunya Conservative and symptomatic treatment pigmentation Drug induced No treatment required (condition is reversible)

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