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Hyperpigmentation

By

Shinjita Das

, MD, Harvard Medical School

Reviewed/Revised Oct 2022
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Topic Resources

Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition.

Focal hyperpigmentation is most often postinflammatory in nature, occurring after injury (eg, cuts Lacerations Lacerations are tears in soft body tissue. Care of lacerations Enables prompt healing Minimizes risk of infection Optimizes cosmetic results read more and burns Burns Burns are injuries of skin or other tissue caused by thermal, radiation, chemical, or electrical contact. Burns are classified by depth (superficial and deep partial-thickness, and full-thickness)... read more Burns ) or other causes of inflammation (eg, acne Acne Vulgaris Acne vulgaris is the formation of comedones, papules, pustules, nodules, and/or cysts as a result of obstruction and inflammation of pilosebaceous units (hair follicles and their accompanying... read more Acne Vulgaris , lupus Systemic Lupus Erythematosus (SLE) Systemic lupus erythematosus is a chronic, multisystem, inflammatory disorder of autoimmune etiology, occurring predominantly in young women. Common manifestations may include arthralgias and... read more Systemic Lupus Erythematosus (SLE) ). Focal linear hyperpigmentation is commonly due to phytophotodermatitis, which is a phototoxic reaction that results from ultraviolet light combined with psoralens (specifically furocoumarins) in plants (eg, limes, parsley, celery— see Chemical photosensitivity Chemical photosensitivity Chemical photosensitivity ). Focal hyperpigmentation can also result from neoplastic processes (eg, lentigines Lentigines Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition. (See also Overview of Pigmentation Disorders.) Focal... read more Lentigines , melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With metastasis... read more Melanoma ), melasma Melasma (Chloasma) Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition. (See also Overview of Pigmentation Disorders.) Focal... read more Melasma (Chloasma) , freckles, or café-au-lait macules Lesion Type (Primary Morphology) Lesion Type (Primary Morphology) . Acanthosis nigricans causes focal hyperpigmentation and a velvety plaque most often on the axillae and posterior neck.

Melasma (Chloasma)

Melasma consists of dark brown, roughly symmetric patches of hyperpigmentation with irregular borders on the face (usually on the forehead, temples, cheeks, cutaneous upper lip, or nose). It occurs primarily in pregnant women (melasma gravidarum, also called the mask of pregnancy) and in women taking oral contraceptives Oral Contraceptives Oral contraceptives (OCs) are steroid hormones that inhibit the release of gonadotropin-releasing hormone (GnRH) by the hypothalamus, thus inhibiting the release of the pituitary hormones that... read more . Ten percent of cases occur in nonpregnant women and dark-skinned men. Melasma is more prevalent among and lasts longer in people with dark skin.

Because melasma risk increases with increasing sun exposure, the mechanism probably involves overproduction of melanin by hyperfunctional melanocytes. Other than sun exposure, aggravating factors include

  • Autoimmune thyroid disorders

  • Photosensitizing drugs

In women, melasma fades slowly and incompletely after childbirth or cessation of hormone use. In men, melasma rarely fades.

The mainstay of melasma management is strict photoprotection agents. Patients should use sunscreen with a sun protection factor (SPF) of 30 or higher, wear protective clothing and hats, and avoid direct sun exposure. During and after therapy, strict sun protection must be maintained. Because visible light is not blocked by most sunscreens, patients should use a tinted sunscreen (eg, that contains zinc oxide or titanium dioxide). The addition of antioxidants to the sunscreen and oral adjunctive photoprotection agents such as Polypodium leucotomas can enhance protection (1 Melasma references Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition. (See also Overview of Pigmentation Disorders.) Focal... read more Melasma references , 2 Melasma references Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition. (See also Overview of Pigmentation Disorders.) Focal... read more Melasma references ). Because of potential health and environmental toxicities, oxybenzone and benzophenone-3 are usually not preferred sunscreens (3 Melasma references Hyperpigmentation has multiple causes and may be focal or diffuse. Most cases are due to an increase in melanin production and deposition. (See also Overview of Pigmentation Disorders.) Focal... read more Melasma references ).

Other treatment depends on whether the pigmentation is epidermal or dermal; epidermal pigmentation becomes accentuated with a Wood light Wood Light Diagnostic tests are indicated when the cause of a skin lesion or disease is not obvious from history and physical examination alone. These include Patch testing Biopsy Scrapings Examination... read more Wood Light (365 nm) or can be diagnosed with biopsy. Only epidermal pigmentation responds to treatment. Most topical melasma treatments are used in combination rather than individually.

Triple topical therapy is first-line treatment that is often effective and consists of a combination of

Hydroquinone depigments the skin by blocking the enzymatic oxidation of tyrosine 3,4-dihydroxyphenylalanine (DOPA) and inhibiting melanocyte metabolic processes. Hydroquinone should be tested behind one ear or on a small patch on the forearm for 1 week before use on the face because it may cause irritation or an allergic reaction. Tretinoin promotes keratinocyte turnover and can exfoliate skin that contains epidermal pigment. Corticosteroids help block synthesis and secretion of melanin. Two promising technologies being tried in conjunction with triple topical therapy are the Q-switched Nd:YAG (1064 nm) laser and nonablative fractional resurfacing.

If triple topical therapy is not available, then hydroquinone 3 to 4% applied twice a day for up to 8 weeks at a time (chronic continuous use can theoretically increase the risk of exogenous ochronosis, which is a permanent form of hyperpigmentation) may be considered; 2% hydroquinone is useful as maintenance.

Azelaic acid 15 to 20% cream can be used in place of or with hydroquinone and/or tretinoin. Azelaic acid is a tyrosinase inhibitor that reduces melanin production. In addition, topical kojic acid has been increasingly used; it is a chelating agent that blocks tyrosine conversion to melanin.

During pregnancy, azelaic acid 15 to 20% cream and chemical peeling with glycolic acid are safe to use. Hydroquinone and tretinoin are not safe to use.

Second-line treatment options for patients with severe melasma unresponsive to topical bleaching agents include chemical peeling with glycolic acid or 30 to 50% trichloroacetic acid. Laser treatments also have been used but are not standard therapy.

Melasma references

  • 1. Goh CL, Chuah SY, Tien S, et al: Double-blind, placebo-controlled trial to evaluate the effectiveness of Polypodium leucotomos extract in the treatment of melasma in Asian skin: A pilot study. J Clin Aesthet Dermatol 11(3):14-19, 2018. Epub 2018 Mar 1. PMID: 29606995; PMCID: PMC5868779

  • 2. Lim HW, Kohli I, Ruvolo E, et al: Impact of visible light on skin health: The role of antioxidants and free radical quenchers in skin protection. J Am Acad Dermatol 86(3S):S27-S37, 2022. doi: 10.1016/j.jaad.2021.12.024

  • 3. DiNardo JC, Downs CA: Dermatological and environmental toxicological impact of the sunscreen ingredient oxybenzone/benzophenone-3. J Cosmet Dermatol 17(1):15-19. doi: 10.1111/jocd.12449

  • 4. Del Rosario E, Florez-Pollack S, Zapata L Jr, et al: Randomized, placebo-controlled, double-blind study of oral tranexamic acid in the treatment of moderate-to-severe melasma. J Am Acad Dermatol 78(2):363–369, 2018. doi: 10.1016/j.jaad.2017.09.053

Lentigines

Lentigines (singular: lentigo) are flat, tan to brown, oval macules. They are commonly due to chronic sun exposure (solar lentigines; sometimes called liver spots but are not related to hepatic dysfunction) and occur most frequently on the face and back of the hands. They typically first appear during middle age and increase in number with age. Although progression from lentigines to melanoma has not been established, lentigines are an independent risk factor for melanoma Melanoma Malignant melanoma arises from melanocytes in a pigmented area (eg, skin, mucous membranes, eyes, or central nervous system). Metastasis is correlated with depth of dermal invasion. With metastasis... read more Melanoma .

If lentigines are a cosmetic concern, they are treated with cryotherapy or laser; hydroquinone is not effective.

Nonsolar lentigines are sometimes associated with systemic disorders, such as Peutz-Jeghers syndrome Peutz-Jeghers Syndrome Peutz-Jeghers syndrome is an autosomal dominant disease with multiple hamartomatous polyps in the stomach, small bowel, and colon along with distinctive pigmented skin lesions. Most (66 to 94%)... read more Peutz-Jeghers Syndrome (in which profuse lentigines of the lips occur), multiple lentigines syndrome (or LEOPARD syndrome, which stands for multiple Lentigines, Electrocardiogram [ECG] conduction abnormalities, Ocular hypertelorism, Pulmonic stenosis, Abnormal genitals, Retardation of growth, and sensorineural Deafness), or xeroderma pigmentosum.

Drug-Induced Hyperpigmentation

Changes are usually diffuse but sometimes have drug-specific distribution patterns or hues ( see Table: Hyperpigmentation Effects of Some Drugs and Heavy Metals Hyperpigmentation Effects of Some Drugs and Heavy Metals Hyperpigmentation Effects of Some Drugs and Heavy Metals ). Mechanisms include

  • Increased melanin in the epidermis (tends to be more brown)

  • Increased melanin in the epidermis and high dermis (mostly brown with hints of gray or blue)

  • Increased melanin in the dermis (tends to be more grayish or blue)

  • Dermal deposition of the drug, metabolite, or drug–melanin complexes (usually slate or bluish gray)

Table

In fixed drug eruptions, red plaques or blisters form at the same site each time the causative drug is taken; residual postinflammatory hyperpigmentation usually persists, especially in darker skin types. Typical lesions occur on the face (especially the lips), hands, feet, and genitals. Typical inciting drugs include antibiotics (sulfonamides, tetracyclines, trimethoprim, and fluoroquinolones), nonsteroidal anti-inflammatory drugs, and barbiturates.

Key Points

  • Common causes of focal hyperpigmentation include injury, inflammation, phytophotodermatitis, lentigines, melasma, freckles, café-au-lait macules, and acanthosis nigricans.

  • Common causes of widespread hyperpigmentation include melasma, drugs, cancers, and other systemic disorders.

  • Test patients who have widespread hyperpigmentation not caused by drugs for disorders such as primary biliary cholangitis, hemochromatosis, and Addison disease.

  • Treat melasma initially with a combination of hydroquinone 2 to 4%, tretinoin 0.05 to 1%, and a class V to VII topical corticosteroid.

  • If lentigines are a cosmetic concern, treat with cryotherapy or laser.

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