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 and burns) or other causes of inflammation (eg, acne, lupus). 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). Focal hyperpigmentation can also result from neoplastic processes (eg, lentigines, melanoma), melasma, or café-au-lait macules. Acanthosis nigricans causes focal hyperpigmentation and a velvety plaque most often on the axillae and posterior neck.

Diffuse hyperpigmentation can result from drugs and also has systemic and neoplastic causes (especially lung carcinomas and melanoma with systemic involvement). After eliminating drugs as a cause of diffuse hyperpigmentation, patients should be tested for the most common systemic causes. These causes are Addison disease (see Adrenal Disorders: Addison Disease), hemochromatosis (see Iron Overload: Hereditary Hemochromatosis), and primary biliary cirrhosis (see Fibrosis and Cirrhosis: Primary Biliary Cirrhosis (PBC)). Skin findings are nondiagnostic; therefore, a skin biopsy is not necessary or helpful.

Melasma (chloasma): Melasma consists of dark brown, sharply marginated, roughly symmetric patches of hyperpigmentation on the face (usually on the forehead, temples, cheeks, upper lip, or nose). It occurs primarily in pregnant women (melasma gravidarum, or the mask of pregnancy) and in women taking oral contraceptives. Ten percent of cases occur in non-pregnant 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.

Treatment depends on whether the pigmentation is epidermal or dermal; epidermal pigmentation becomes accentuated with a Wood light or can be diagnosed with biopsy. Only epidermal pigmentation responds to treatment. First-line therapy, often effective, includes a combination of hydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
2 to 4%, tretinoinSome Trade Names
RETIN-A
Click for Drug Monograph
0.05 to 1%, and a class V to VII topical corticosteroid (Table 1: Principles of Topical Dermatologic Therapy: Relative Potency of Selected Topical Corticosteroids ). HydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
3 to 4% applied twice daily is usually required for long courses; 2% hydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
is useful as maintenance. HydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
should be tested behind one ear or on a small patch on the forearm for 1 wk before use on the face because it may cause irritation or an allergic reaction. Azelaic acidSome Trade Names
AZELEX
FINACEA
Click for Drug Monograph
15 to 20% cream, can be used in place of or with hydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
and/or tretinoinSome Trade Names
RETIN-A
Click for Drug Monograph
. HydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
, tretinoinSome Trade Names
RETIN-A
Click for Drug Monograph
, and azaleic acid are bleaching agents. Chemical peeling with glycolic acid or 30 to 50% trichloroacetic acid is an option for patients with severe melasma unresponsive to topical bleaching agents. Laser treatments have been used, but none has been established yet as standard therapy. Two promising technologies are the Q-switched Nd:YAG (1064 nm) laser and nonablative fractional resurfacing in conjunction with triple topical therapy as described above. During and following therapy, strict sun protection must be maintained.

Lentigines: Lentigines (singular: lentigo) are flat, tan to brown, oval spots. They are commonly due to chronic sun exposure (solar lentigines; sometimes called liver spots) 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. If lentigines are a cosmetic concern, they are treated with cryotherapy or laser; hydroquinoneSome Trade Names
CLARIPEL
ELDOQUIN
SOLAQUIN
Click for Drug Monograph
is not effective.

Nonsolar lentigines are sometimes associated with systemic disorders, such as Peutz-Jeghers syndrome (in which profuse lentigines of the lips occur), multiple lentigines syndrome (Leopard syndrome), or xeroderma pigmentosum.

Drug-induced hyperpigmentation: Changes are usually diffuse but sometimes have drug-specific distribution patterns or hues (see Table 1: Pigmentation Disorders: Hyperpigmentation Effects of Some Drugs and Chemicals). Mechanisms include

Table 1
PrintOpen table in new window
Hyperpigmentation Effects of Some Drugs and Chemicals Substance Effect Drugs AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph Slate-gray to violaceous discoloration of sun-exposed areas; yellowish-brown deposits in the dermis Antimalarials Yellow-brown to gray to bluish black discoloration of pretibial areas, face, oral cavity, and nails; drug–melanin complexes in the dermis; hemosiderin around capillaries BleomycinSome Trade Names BLENOXANE Click for Drug Monograph Flagellate hyperpigmented streaks on the back, often in areas of scratching or minor trauma Cancer chemotherapy drugs, including busulfanSome Trade Names MYLERAN Click for Drug Monograph , cyclophosphamideSome Trade Names CYTOXAN Click for Drug Monograph , dactinomycinSome Trade Names COSMEGEN Click for Drug Monograph , daunorubicinSome Trade Names CERUBIDINE Click for Drug Monograph , and 5-fluorouracilSome Trade Names ADRUCIL Click for Drug Monograph (5-FU) Diffuse hyperpigmentation DesipramineSome Trade Names NORPRAMIN Click for Drug Monograph ImipramineSome Trade Names TOFRANIL Click for Drug Monograph Grayish blue discoloration on sun-exposed areas; golden-brown granules in upper dermis HydroquinoneSome Trade Names CLARIPEL ELDOQUIN SOLAQUIN Click for Drug Monograph Bluish black discoloration of ear cartilage and face after years of use Phenothiazines, including chlorpromazineSome Trade Names THORAZINE Click for Drug Monograph Grayish blue discoloration on sun-exposed areas; golden-brown granules in upper dermis Tetracyclines, particularly minocyclineSome Trade Names MINOCIN Click for Drug Monograph Grayish discoloration of teeth, nails, sclerae, oral mucosa, acne scars, face, forearms, and lower legs Heavy metals Bismuth Blue-gray discoloration of face, neck, and hands Gold Blue-gray deposits around the eyes (chrysiasis) Mercury Slate-gray discoloration of skinfolds Silver Diffuse slate-gray discoloration (argyria), especially in sun-exposed areas Hyperpigmentation Effects of Some Drugs and Chemicals Substance Effect Drugs AmiodaroneSome Trade Names CORDARONE Click for Drug Monograph Slate-gray to violaceous discoloration of sun-exposed areas; yellowish-brown deposits in the dermis Antimalarials Yellow-brown to gray to bluish black discoloration of pretibial areas, face, oral cavity, and nails; drug–melanin complexes in the dermis; hemosiderin around capillaries BleomycinSome Trade Names BLENOXANE Click for Drug Monograph Flagellate hyperpigmented streaks on the back, often in areas of scratching or minor trauma Cancer chemotherapy drugs, including busulfanSome Trade Names MYLERAN Click for Drug Monograph , cyclophosphamideSome Trade Names CYTOXAN Click for Drug Monograph , dactinomycinSome Trade Names COSMEGEN Click for Drug Monograph , daunorubicinSome Trade Names CERUBIDINE Click for Drug Monograph , and 5-fluorouracilSome Trade Names ADRUCIL Click for Drug Monograph (5-FU) Diffuse hyperpigmentation DesipramineSome Trade Names NORPRAMIN Click for Drug Monograph ImipramineSome Trade Names TOFRANIL Click for Drug Monograph Grayish blue discoloration on sun-exposed areas; golden-brown granules in upper dermis HydroquinoneSome Trade Names CLARIPEL ELDOQUIN SOLAQUIN Click for Drug Monograph Bluish black discoloration of ear cartilage and face after years of use Phenothiazines, including chlorpromazineSome Trade Names THORAZINE Click for Drug Monograph Grayish blue discoloration on sun-exposed areas; golden-brown granules in upper dermis Tetracyclines, particularly minocyclineSome Trade Names MINOCIN Click for Drug Monograph Grayish discoloration of teeth, nails, sclerae, oral mucosa, acne scars, face, forearms, and lower legs Heavy metals Bismuth Blue-gray discoloration of face, neck, and hands Gold Blue-gray deposits around the eyes (chrysiasis) Mercury Slate-gray discoloration of skinfolds Silver Diffuse slate-gray discoloration (argyria), especially in sun-exposed areas

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

Drugs may cause secondary hyperpigmentation. For example, focal hyperpigmentation frequently occurs after drug-induced lichen planus (also known as lichenoid drug reactions).

In fixed drug eruptions, red plaques or blisters form at the same site each time a drug is taken; residual postinflammatory hyperpigmentation usually persists. Typical lesions occur on the face (especially the lips), hands, feet, and genitals. Typical inciting drugs include sulfonamides, tetracyclineSome Trade Names
ACHROMYCIN V
TETRACYN
TETREX
Click for Drug Monograph
, NSAIDs, barbiturates, and carbamazepineSome Trade Names
TEGRETOL
Click for Drug Monograph
.

Key Points

• Common causes of focal hyperpigmentation include injury, inflammation, phytophotodermatitis, lentigines, melasma, 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 primary biliary cirrhosis, hemochromatosis, and Addison disease.
• Treat melasma initially with a combination of hydroquinoneSome Trade Names
  CLARIPEL
  ELDOQUIN
  SOLAQUIN
  Click for Drug Monograph
  2 to 4%, tretinoinSome Trade Names
  RETIN-A
  Click for Drug Monograph
  0.05 to 1%, and a class V to VII topical corticosteroid.
• If lentigines are a cosmetic concern, treat with cryotherapy or laser.

Last full review/revision November 2012 by Peter C. Schalock, MD

Content last modified December 2012