INTRODUCTION — Skin-lightening (or "skin-bleaching") agents are essential tools in the management of disorders of hyperpigmentation, such as melasma and postinflammatory hyperpigmentation. However, some skin-lightening practices and ingredients can result in multiple short- and long-term complications. Examples include irritant contact dermatitis, exogenous ochronosis, mercury toxicity, cutaneous atrophy, and adrenal insufficiency.
The availability of skin-lightening formulations that are not regulated, that contain ingredients that are illegal to sell without a prescription, or that contain ingredients not intended for cutaneous use contributes to the development of complications. Adverse events may also result from prolonged or excessive use of approved skin-lightening formulations.
Early recognition of signs associated with skin-lightening agent misuse is important in reducing long-term sequelae. The complications associated with misuse of skin-lightening agents will be reviewed here. Prescribed use of skin-lightening agents for the treatment of cutaneous hyperpigmentation is reviewed separately. (See "Melasma: Management" and "Postinflammatory hyperpigmentation", section on 'Medical treatment'.)
PREVALENCE OF SKIN LIGHTENING — Skin lightening is a global phenomenon, with the highest rates in Africa, Asia, the Caribbean, and the Middle East, as well as in immigrant populations from these regions in North America and Europe [1-6].
Studies in some populations have reported relatively high rates of use of skin-lightening agents; for example, a South African survey of female patients (Fitzpatrick skin phototype IV or higher (table 1)) who visited two general outpatient hospital departments in Durban found that 187 of 571 (33 percent) reported use of skin-lightening products. In addition, a Ghanaian study of 555 individuals (primarily female) in fishing communities in Accra found a prevalence of use of skin-lightening products of 50 percent [4,5]. Reports from Asia, North America, Europe, and Latin America have also demonstrated complications associated with skin-lightening agents in populations where the practice is prevalent [1,3,7-12].
MOTIVATION FOR SKIN LIGHTENING — The skin-lightening industry is a multibillion dollar industry [13,14]. The industry encompasses both use for the treatment of pigmentary disorders and use for the purpose of lightening natural skin pigmentation, with geographic variance in the proportions associated with these indications :
●Cultural and commercial beauty ideals – The widespread practice of skin lightening stems from cultural and commercial beauty ideals, many of which are propagated by media using local models with lightly pigmented skin [15,16]. In numerous cultures, less skin pigmentation is frequently equated with higher social status and physical attractiveness due, at least in part, to complex, historical, sociopolitical factors.
●Social factors – Certain social factors may influence the likelihood of skin-lightening practices. A questionnaire-based study of skin-lightening practices among 76 female adults in New York City who had utilized skin-lightening products for at least one year found associations between certain social factors and the intensity of skin-lightening practices . In particular, female adults with lower education status and females who were born outside of the United States were more likely to report a longer duration of skin-lightening practices and daily use of skin-lightening products.
Influence from close personal relationships may contribute to skin-lightening practices. A survey of 348 undergraduate females in Sudan found that the women were more likely to engage in skin lightening if a family member engaged in skin lightening or if they were dissatisfied with skin color .
●Psychologic factors – A questionnaire-based study of 1226 young adults from Jamaica, Barbados, and Grenada found associations between use of skin-lightening agents and a history of abuse as a child, symptoms of trauma, and significant depression .
AGENTS — Skin-lightening agents commonly found in regulated and unregulated skin-lightening products that can cause complications include hydroquinone, corticosteroids, mercury salts, and caustic agents:
●Mechanisms of action – The mechanism of action of hydroquinone involves inhibition of tyrosinase activity, which inhibits the conversion of dihydroxyphenylalanine to melanin. Topical corticosteroids and mercury salts have inhibitory effects on melanogenesis . Caustic agents such as hydrogen peroxide may inhibit melanin production through toxic effects on melanocytes.
●Availability – In the United States, products that contain skin-lightening agents, such as hydroquinone and topical corticosteroids, are legally available as both prescription and nonprescription products. When used appropriately, risk for complications from such agents is low.
However, unregulated skin-lightening products that contain unapproved ingredients or unapproved concentrations of ingredients can be obtained without a prescription in the United States and other countries. These products are typically purchased from small convenience stores, cosmetic shops, and street vendors . In the United States, such products are usually imported by international companies or smuggled into areas where the demand is high . Skin-lightening formulations containing unregulated ingredients can also be purchased via the internet worldwide.
●Inaccurate product labeling and inclusion of caustic substances – Clinicians should be aware that ingredient lists provided on or in packages of skin-lightening agents are not always accurate. A study examining the active ingredients in the 10 best-selling skin-lightening creams in Durban, South Africa, found that nearly one-half of the analyzed products contained mercury as an active ingredient, although this was not listed on the label or package insert .
In addition, according to the US Food and Drug Administration, cosmetics and skin-bleaching preparations should contain no more than a trace amount of mercury, defined as less than 1 part per million (ppm) . However, concentrations well above this limit have been found in numerous skin-lightening creams sold in the United States and internationally. In one study of 549 skin-lightening products, 6 percent contained mercury above 1000 ppm . Moreover, a study assessing mercury concentrations in spot urine specimens from a representative sample of 1840 adult New Yorkers found that mercury-containing skin-lightening creams were a source of exposure in individuals with the highest levels of mercury in the urine .
In some instances (particularly in sub-Saharan Africa), ingredients from the domestic environment (toothpaste, washing liquid, washing soda, hair straighteners, sand, cement, and even battery fluid) are mixed in homemade skin-bleaching concoctions for their caustic effect [1,20,24].
COMPLICATIONS — Misuse of skin-lightening agents can result in a variety of local and systemic adverse effects. Adverse effects related to hydroquinone, mercury, and topical corticosteroids in skin-lightening agents are reviewed below.
Hydroquinone — While hydroquinone is a safe and effective treatment for a broad range of disorders of hyperpigmentation, risk for acute and chronic complications increases in association with protracted administration, use of high concentrations, mixture with other ingredients that enhance dermal absorption (eg, resorcinol), and application to large body surface areas. Potential complications include short-term cutaneous side effects, exogenous ochronosis, abnormal skin repigmentation, darker pigmentation of skin overlying finger and toe joints, and trimethylaminuria.
Short-term cutaneous complications — Irritant contact dermatitis, typically from concentrations higher than 4 percent or when mixed with caustic additives to increase absorption, is the most common short-term adverse event associated with hydroquinone and may result in postinflammatory dyspigmentation. Hydroquinone may also induce allergic contact dermatitis .
Exogenous ochronosis — Excessive or long-term use of hydroquinone can lead to exogenous ochronosis:
●Clinical manifestations – Exogenous ochronosis most often manifests as asymptomatic, blue-black macules and patches, most commonly on the cheeks, temples, and neck (picture 1A-C) . Three clinical stages of exogenous ochronosis have been described: erythema and mild pigmentation; hyperpigmentation, black colloid milia, and scanty atrophy; and papulonodules with or without surrounding inflammation . Unlike its endogenous form (alkaptonuria), exogenous ochronosis lacks any systemic complications or urinary abnormalities. (See "Disorders of tyrosine metabolism", section on 'Alkaptonuria'.)
●Diagnosis – The pathogenesis of exogenous ochronosis may involve inhibition of homogentisic acid oxidase leading to the accumulation of homogentisic acid in the skin, which then polymerizes to form the ochronotic deposits in the dermis . A skin biopsy (eg, 3 or 4 mm punch biopsy) demonstrating yellow-brown, banana-shaped fibers in the papillary dermis is the gold standard for diagnosis (picture 2). The ochronotic fibers stain black with Fontana stain and blue-black with methylene blue stain [26,28]. Dermoscopy can also be a useful diagnostic tool; amorphous, densely pigmented structures obliterating follicular openings can be observed [29,30].
●Management – Exogenous ochronosis may improve slowly after stopping the offending lightening agent  but is generally considered permanent. There have been positive results with quality-switched (Q-switched) ruby laser, 755 nm Q-switched alexandrite laser, combination dermabrasion plus carbon dioxide (CO2) laser, 1064 nm neodymium-doped yttrium aluminum garnet (Nd:YAG) laser, and cryotherapy [26,32-34]. Other studies have shown no improvement [29,32]. In the author's experience, nonablative fractional laser resurfacing can improve the appearance of exogenous ochronosis but can induce postinflammatory hyperpigmentation. Topical retinoic acid and combination treatments including retinoic acid have been attempted with mixed results [7,29,35].
Other side effects — Additional potential side effects of hydroquinone misuse include:
●Abnormal skin repigmentation – Abnormal repigmentation of skin can occur, particularly in sun-exposed areas. This typically manifests as mottled hyperpigmentation on the malar area, dorsal extremities, and/or upper trunk.
●Hyperpigmentation of the finger joints and toes – Hyperpigmentation of the finger joints (especially the distal and proximal interphalangeal joints) and toes relative to the dorsal hands and feet is a common sequela of skin bleaching of the hands and feet with hydroquinone . This likely represents residual, normal pigmentation as opposed to increased pigment production.
●Trimethylaminuria – Trimethylaminuria, also known as "fish odor syndrome," has been reported among chronic users of skin-bleaching creams containing hydroquinone. This is characterized by a rotten fish odor in the breath, urine, and body due to excretion of trimethylamine in body fluids .
Mercury — Complications of exposure to mercury through misuse of skin-lightening agents include cutaneous, renal, and neuropsychiatric abnormalities .
Cutaneous complications — Cutaneous complications of mercury-containing skin-lightening formulations include contact dermatitis, erythroderma, flushing, purpura, gingivostomatitis, gray or blue-black facial discoloration (paradoxical hyperpigmentation) secondary to dermal deposition of mercury-containing granules, and nail discoloration [25,39].
Mercury toxicity — Systemic exposure to inorganic mercury or mercury salts can occur as a result of cutaneous absorption or inadvertent oral ingestion (eg, from use of mercury-containing cosmetics near the mouth or from hand-to-mouth contact) . The rate of dermal absorption of inorganic mercury is proportional to the concentration of mercury and prior hydration of the skin. Dermal absorption is increased when mercury-containing cosmetics are formulated in lipid-soluble vehicles or applied to compromised skin .
Once absorbed, inorganic mercury is distributed widely and is eliminated primarily through urinary excretion and the feces . Systemic complications include proteinuria, nephrotic syndrome, renal tubular acidosis, tremor, muscle weakness, peripheral neuropathy, metallic taste, hypersalivation, memory loss, erethism, depression, anxiety, and psychosis (eg, "mad hatter's disease") [8,13,25,39,41-43]. Mercury exposure during pregnancy may adversely affect neurologic and cognitive development of the fetus . The manifestations, diagnosis, and management of mercury toxicity are reviewed in detail separately. (See "Mercury toxicity", section on 'Inorganic mercury salts toxicity'.)
Topical corticosteroids — Use of skin-lightening creams that contain corticosteroids, particularly unregulated formulations containing high-potency agents such as clobetasol propionate, fluocinonide, and betamethasone dipropionate, can lead to adverse cutaneous and systemic effects. Patients are typically unaware that their skin-lightening products contain corticosteroids; therefore, recognition of the characteristic signs and symptoms of corticosteroid excess is critical for diagnosis.
Cutaneous complications — Common cutaneous manifestations of long-term use of skin-lightening agents containing corticosteroids include atrophy, striae, folliculitis (especially near the axillae), acne, tinea corporis, hypertrichosis, purpura, hypopigmentation, and persistent erythema (picture 3) [19,36]. In particular, tinea corporis may be extensive and may present with an atypical appearance (tinea incognito). (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
Systemic complications — Prolonged administration of topical corticosteroids and application to large body surface areas increases the risk for systemic absorption and associated complications. Systemic complications of corticosteroid-containing skin-lightening creams, particularly when used for large-scale skin lightening, include hyperglycemia, hypothalamic-pituitary-adrenal axis suppression, Cushing's syndrome, hypertension, and avascular necrosis of the femoral head [19,36,45,46]. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)
PATIENT EVALUATION AND MANAGEMENT — Cultural sensitivity is paramount when asking patients about use of skin-lightening agents and recommending their discontinuation.
Recognition of at-risk patients — Early recognition of use of skin-lightening agents is important for minimizing risk for complications.
Examples of incidental physical findings that raise suspicion for use of skin-lightening agents include:
●A paradoxically lighter appearance of the face compared with sun-protected areas
●Islands of normal pigment over the joints in the context of diffuse lightening of the hands
Commonly, patients present with signs of cutaneous or systemic complications that lead to recognition of skin-lightening agent use (eg, skin darkening related to hydroquinone, acne exacerbations or striae related to topical corticosteroids, or systemic symptoms). (See 'Hydroquinone' above and 'Mercury' above and 'Topical corticosteroids' above.)
Confirming use of skin-lightening agents — Recognizing that there are cultural factors, individual factors, and potential feelings of shame associated with the practice of skin lightening, the patient interview should be conducted with sensitivity. Directly asking if a patient is "bleaching their skin" or "trying to lighten their skin color" may be perceived as judgemental or confrontational. Use of open-ended and nonjudgmental questions is preferred. Examples include:
●"For accurate diagnosis, it is helpful to know all of the products you have used on your skin in the past year or so. Can we review all of the skin care products you are using, even those you only use occasionally?"
●"Some skin care products include ingredients that can cause this problem on the skin. So that I can be the most helpful, can we review all of the products you are using on your skin?"
●"Does your skin care routine include any products to help even out your skin tone, brighten your skin, or improve the appearance of your skin?"
Asking the patient to bring all of their skin care products to the next appointment is also helpful, if feasible.
Interventions — The goal of intervention is to minimize risk from adverse effects associated with prolonged use of skin-lightening agents. Key interventions include patient counseling to encourage cessation of misuse and the management of complications.
Patient counseling — Once use of a skin-lightening agent has been determined, we encourage cessation of use and counsel patients on the potential adverse local and systemic effects of excessive or protracted use of skin-lightening agents, especially unregulated formulations. Sensitivity is important. We find the following approaches helpful for preserving the clinician-patient relationship and increasing the likelihood of adherence to clinician recommendations:
●Avoid assigning or implying blame on the patient or challenging their personal beauty ideals
●Discuss the shared goal of ensuring long-term skin health and preventing adverse effects in a nonjudgmental manner
●Make an effort to understand the patient's aesthetic goals or concerns
●Offer safer therapies for specific skin concerns or underlying skin disorders
Assessment for mercury toxicity — Given the potential serious complications of mercury exposure, an assessment for mercury toxicity is indicated for all patients with a history of excessive use of unregulated skin-lightening agents (eg, use on a large proportion of the body surface area or prolonged use). If the clinical presentation or a review of systems suggests the possibility of mercury toxicity, further evaluation is indicated. (See 'Mercury toxicity' above and "Mercury toxicity", section on 'Diagnosis' and "Mercury toxicity", section on 'Clinical manifestations'.)
Management of complications — Cessation of use of the skin-lightening agent is often the most important factor in minimizing progression of complications and improving reversible complications. (See 'Complications' above.)
Specific additional interventions may be helpful for some complications, such as antifungal therapy for corticosteroid-related tinea infections, laser therapy for exogenous ochronosis, or interventions for mercury toxicity. (See 'Topical corticosteroids' above and 'Hydroquinone' above and 'Mercury' above.)
SUMMARY AND RECOMMENDATIONS
●Overview – Skin lightening (or skin bleaching) refers to the practice of using depigmenting agents to lighten the color of skin. Skin lightening is a global phenomenon that is most prevalent in Africa, Asia, the Caribbean, the Middle East, and Central/South America, as well as in immigrant populations in North America, Europe, and elsewhere. (See 'Prevalence of skin lightening' above.)
●Agents – Skin-lightening agents associated with complications most commonly contain hydroquinone, mercury, corticosteroids, and caustic agents. Ingredient lists on packages are frequently inaccurate; in particular, products containing mercury may not list mercury as an ingredient. (See 'Agents' above.)
●Complications – Use of skin-lightening agents may be associated with multiple cutaneous side effects, such as irritant contact dermatitis, exogenous ochronosis, cutaneous atrophy, and skin dyspigmentation. Serious systemic side effects, such as mercury toxicity, Cushing's disease, and adrenal crisis, can also occur. (See 'Complications' above.)
●Recognition – Early recognition of the signs of misuse of skin-lightening agents is essential to prevent long-term or permanent local and/or systemic complications. Patients are often unaware that they are using products containing high-potency corticosteroids and other potentially harmful ingredients. (See 'Recognition of at-risk patients' above.)
●Importance of cultural sensitivity – Inquiring about and counseling patients on use of skin-lightening agents should be performed with sensitivity. A variety of factors contribute to use of skin-lightening agents, and taking a nonjudgmental approach is valuable for communicating with patients. (See 'Patient evaluation and management' above.)
●Management – The management of skin-lightening agent misuse consists of patient education, prompt discontinuation of the skin-lightening agent, and interventions to improve specific complications. In addition, patients with a history of excessive use of skin-lightening agents should be evaluated for mercury toxicity. (See 'Interventions' above.)
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