Ochronosis

Abstract

Hyperpigmentation disorders are common and include a multitude of forms. They are typically divided into three large categories: dermal, epidermal, or mixed, depending on the site of abnormality. The location of the increased melanin affects treatment options, but therapy within a group is often similar. This paper discusses the treatment modalities, including topical and surgical approaches, available for the different types of hyperpigmentation.

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Introduction

Hyperpigmentation is a darkening of the skin, which typically results from increased melanin. This may occur in the epidermis, dermis, or both (Figures 1 and 2). Either increased melanin production by existing melanocytes (melanotic hyperpigmentation) or proliferation of active melanocytes (melanocytic hyperpigmentation) is responsible.

[FIGURE 1 OMITTED]

Clinically, the lesions may appear as localized, circumscribed spots or in a more diffuse pattern. With diffuse involvement, the lesions may be scattered discrete macules, reticulated macules, or ill-defined. Epidermal involvement appears as brown discoloration, dermal as blue-gray, and mixed epidermal and dermal as brown-gray. Although these disorders can affect any site, certain diseases have a predilection for specific anatomic locations. For example, melasma generally involves the face, acral melanosis affects the hands, and tinea versicolor targets the trunk.

The topic of hyperpigmentation encompasses too many disorders to go into any great detail within this review article. However, many of the same therapies are used among all of the various hyperpigmentation disorders. This paper focuses on these treatment options.

Epidemiology

Hyperpigmentation disorders of the skin are common. Although they typically affect all races, some forms, such as melasma and postinflammatory hyperpigmentation, are more prevalent in darker-complexioned individuals. A survey conducted by Halder et al revealed that, of 2,000 black patients seeking dermatologic care in a private-practice setting, pigmentary problems other than vitiligo were cited as the third most common skin disorder (1). On the other hand, solar lentigines are more common in those with Fitzpatrick skin types I-III. In fact, 90% of white adults older than 60 years of age possess these "age" spots (2). Age at the time of onset varies between specific disorders and ranges from as early as birth (i.e., Nevus of Ota) up until late adulthood (i.e., solar lentigines). Prevalence between the sexes also varies. Melasma is much more common in women, whereas Becker's nevus occurs five times more frequently in males.

Differential Diagnosis

Most of the hyperpigmentation disorders can be distinguished clinically. A list of the more common hyperpigmentation disorders is listed in Table 1. This table divides the conditions into epidermal (superficial) and dermal (deep) pigment disorders, and further classifies them as melanotic or melanocytic. Most of the epidermal and dermal pigment disorders are due to increased melanin production with normal melanocyte numbers (melanotic hyperpigmentation); however, other pigment disorders, such as lentigines, Mongolian spots, and Nevus of Ota, may result from increased melanocyte numbers (melanocytic hyperpigmentation).

Treatment

Dermal hyperpigmentation

Dermal hyperpigmentation is recalcitrant to many therapeutic interventions. Cover-up with opaque cosmetics remains essentially the only option for aesthetically displeasing discolorations such as dermal melasma. An exception to this was reported in a pilot study of pulsed CO2 laser followed by Q-switched alexandrite laser in the treatment of dermal melasma that showed promising results (3). Nevus of Ota has effectively been treated with the selective photothermolysis with the Q-switched ruby laser as well. On the other hand, multiple therapies are available in the management of epidermal hyperpigmentation.

Epidermal Hyperpigmentation

Topical therapies

Topical agents commonly utilized in the treatment of hyperpigmentation disorders include phenols (i.e., hydroquinone, mequinol), retinoids (i.e., tretinoin), alpha-hydroxy acids (i.e., glycolic acid), salicylic acid, and azelaic acid. Hydroquinone works by inhibiting the tyrosinase enzyme, thereby preventing the conversion of dopa to melanin. Although a useful depigmenting agent, hydroquinone requires a prolonged treatment course before any significant improvement in the hyperpigmentation (up to 6 months). Most dermatologists recommend 4% hydroquinone, which is prescription strength, but infrequently higher strengths can be compounded. Some authors suggest continuation of low-dose, over-the-counter 2% hydroquinone for melasma maintenance therapy after an initial treatment period (4). Irritant and allergic contact dermatitis, nail discoloration, and postinflammatory hyper- or hypopigmentation are potential side effects (5). Ochronosis (a permanent, reticulated, ripple-like, sooty pigmentation), although uncommon, can occur, particularly after prolonged use of high concentration hydroquinone (6).

Though slow to work (24 weeks or more), tretinoin 0.1% cream can improve melasma and other hyperpigmentary disorders (7-9). Reduction of pigmentation results from the retinoid-induced dispersion of keratinocyte pigment granules, interference with pigment transfer, and acceleration of epidermal turnover (10). Other strengths and formulations (0.05% cream, 0.01% and 0.05% emollient cream) have also been used. Adverse effects include erythema, peeling, and possible postinflammatory hyperpigmentation (6).

Azelaic acid may also be helpful, particularly during pregnancy as it is pregnancy category B. This chemical inhibits DNA synthesis in melanocytes and has a modest antityrosinase effect (2). Comparisons of azelaic acid to 2% hydroquinone revealed superiority with azelaic acid, but no significant difference from 4% hydroquinone (11,12). Pruritus, mild transient erythema, scaling, and burning may occur (13).

Other topical medications have been applied to hyperpigmentation disorders. Attempts with kojic acid demonstrated no more efficacy than other therapies, but more irritation. In one study, premarin cream, a topical conjugated estrogen, improved the appearance of photodamaged skin including the appearance of lentigines (14).

Combination therapy offers the best results. The mixture of tretinoin 0.1%, hydroquinone 5%, and dexamethasone 0.1% (Kligman's formula) yield better results than any of the medications alone, and several adaptations of this regimen have confirmed this finding (10,15,16). A recent trial comparing a triple combination of tretinoin 0.05%, hydroquinone 4%, and fluocinolone acetonide 0.01% in 641 melasma patients demonstrated better results with the triple therapy than any of the dual combinations of the above agents (17). Contrary to monotherapy, clinically significant improvement with the triple therapy was noted as early as 4 weeks with maximum results at 8 weeks (17). Local irritation, which is generally mild, is the most common adverse event. Although the medication is typically only used for 2 to 3 months at a time, this triple therapy has proven safe even with 6 and 12 months of use (18). The addition of tretinoin to topical steroids increases the epidermal skin thickness (19), which may help explain the maintained safety of this drug.

Others have had success in melasma treatment with just the combination of lower concentration hydroquinone 2% and tretinoin 0.5% (4). Lentigines have been successfully managed with the combination of mequinol (a phenolic compound) and tretinoin, the first combination therapy approved for the treatment of solar lentigines. The presence of two different mechanisms of action on the inhibition of the pigmentary process appears to account for the synergy of these two compounds. Fleischer et al found this compound to be more effective for solar lentigines then either agent alone (20). Local irritation is the most common side effect. One study of melasma patients demonstrated a more rapid response (3 months vs. 10 months) with the addition of chemical peels to a tretinoin/hydroquinone regimen (21).

Superficial and medium-depth peels with trichloracetic acid (TCA), glycolic acid, salicylic acid, and tretinoin benefit some individuals. One clinical trial examining the effects of TCA peels noted success with 40% complete regression and 50% partial regression of lentigines (22). Following pretreatment with topical tretinoin and localized 20% TCA, a peel consisting of 50% salicylic acid, methyl salicylate, and croton oil proved efficacious in the treatment of solar lentigines, even after one application (23). Another trial looking at the effects of the addition of glycolic acid peels to a topical regimen of 2% hydroquinone, 10% glycolic acid, and 0.05% tretinoin cream for postinflammatory hyperpigmentation in black patients showed improved results with the peels with minimal adverse effects (24). Benefits of tretinoin peels have also been observed in certain hyperpigmentation disorders, including that of photodamaged skin. In addition, a more rapid response occurs than that observed with topical retinoid creams (25). The addition of glycolic acid peels to a modified Kligman's formula displayed more rapid and greater improvement than the topical regimen alone in melasma patients (26). However, peels must be used with caution in darker pigmented persons because of the greater risk of postinflammatory hyperpigmentation. The association of hypo- and hyperpigmentation, scarring, and keloid formation decreases the utilization of deep peels, especially in dark-complexioned patients (27). Other potential side effects of the chemical peels include atrophy, bacterial and viral infections, milia, telangiectasias, and pore enlargement (28).

Surgical

Dermabrasion is one technique used in the management of hyperpigmentation disorders, but again the increased risk of postinflammatory hyperpigmentation in dark-skinned individuals makes this option less desirable. For many decades, cryosurgery has been employed as a means to treat lentigines. Selective destruction of melanocytes, which are most susceptible to cold, explains the success of cryosurgery. A study looking at cryosurgery compared to local dermabrasion for the treatment of solar lentigo on the back of the hands found comparable results between the two therapies, but less temporary side effects and a faster healing time were noted with dermabrasion (29). However, another clinical trial evaluating liquid nitrogen versus both argon and CO2 lasers demonstrated superiority of the liquid nitrogen (30). Cryosurgery can lead to permanent hypopigmentation. Proper technique, in which one freezes the lesion intermittently for 10 seconds, producing a 1-to-2 millimeter halo around the spot (31), minimizes this risk. Additional possible side effects include erythema, hyperpigmentation, atrophy, and pain.

Therapy with various lasers including erbium yttrium-aluminum-garnet (Er:YAG), Q-switched ruby, dye (510 nm), CO2, argon, and neodymium (Nd:YAG) lasers have been attempted. Thermal injury damages the epidermis and removes the pigmented lesions. To localize tissue destruction to the target lesions and minimize side effects such as textural changes or scarring, lasers such as the frequency-doubled Q-switched Nd:YAG and Q-switched ruby lasers are used. These lasers emit wavelengths that are absorbed more specifically by the targeted tissue and also use shorter pulse durations (specific photothermolysis) (32,33). Melasma is resistant to most lasers. The Er:YAG laser revealed some improvement in melasma, but significant postinflammatory hyperpigmentation requiring 6 months of treatment resulted (34). Goldberg (35) and McBurney (36) demonstrated encouraging responses with the Q-switched ruby laser and the argon laser, but these results were short-lived. In contrast to that of melasma, many of the lasers are successful in the management of solar lentigines, even after a single treatment. The frequency-doubled Q-switched Nd:YAG laser demonstrated better results after one treatment of facial lentigines when compared to 35% trichloracetic acid (37). Another study revealed that the Q-switched ruby laser removed lentigines more effectively and with less irritation than did glycolic acid peels (33). Although decreased pigmentation of solar lentigines with CO2 lasers has been shown (38), the effects are not as impressive as those with cryosurgery and more adverse events may ensue from the nonselective thermal damage. Intense pulsed light (IPL) appears promising as an effective means to treat lentigines with minimal side effects (39,40). Complications of the lasers include atrophy, hypertrophic scarring, and hypo- and hyperpigmentation (6). Because of the melanocyte-destructive nature of techniques, such as cryosurgery (41) and pigmented lesion dye lasers (42), their adverse effects are more likely to be permanent.

Adjuvant

Sunlight exacerbates most hyperpigmentary disorders. Therefore, daily use of sunscreens (SPF at least 15 with both UVA and UVB protection) and avoidance of UV radiation is recommended. When possible, treatment of the underlying process is key. Inciting compounds, such as psoralen-containing vegetables, fruits, plants, cosmetics, and coal tars, should be avoided if photocontact dermatitis is suspected. Patients with primary inflammatory conditions, such as acne and atopic dermatitis, need early intervention to keep the inflammation under tight control, decreasing the risk of post-inflammatory hyperpigmentation. Table 2 summarizes the treatment options for both dermal and epidermal hyperpigmentation disorders.

Funding Source: The Center for Dermatology Research is funded by a grant from Galderma Laboratories, L.P.

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KIMBERLY A CAYCE MD, STEVEN R FELDMAN MD PHD, AMY J MCMICHAEL MD

CENTER FOR DERMATOLOGY RESEARCH, WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE, WINSTON-SALEM, NC

ADDRESS FOR CORRESPONDENCE:

Amy J. McMichael MD

Department of Dermatology

Wake Forest University School of Medicine

Medical Center Boulevard

Winston-Salem, NC 27157

Phone: (336) 716-2768

Fax: (336) 716-7732

E-mail: amcmicha@wfubmc.edu

THE "FOCUS ON:" SECTION IS DESIGNED TO PROVIDE A BACKGROUND ON ONE OF THE BASIC AREAS OF OUR PRACTICE--A COMMON CONDITION, SUBJECT, OR PROCESS WHICH WE AS DERMATOLOGISTS MAY OFTEN DEAL WITH, YET MIGHT NOT INTIMATELY UNDERSTAND. THIS NEW FEATURE WILL APPEAR EACH ISSUE AS AN INFORMATIVE REVIEW OF A DIFFERENT DERMATOLOGICAL TOPIC.

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