Drug-Induced Pigmentation Workup

Updated: Apr 30, 2018
  • Author: David F Butler, MD; Chief Editor: Dirk M Elston, MD  more...
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Laboratory Studies

Many metabolic and endocrine diseases induce pigmentary changes that appear identical to those seen with drug-related etiologies; these alternative etiologies require exclusion, often best achieved through laboratory investigation for genetic mutations or hormonal/electrolyte disturbances. Several situations in which laboratory examination assists in obtaining a patient's diagnosis are discussed below.

Addison disease is the syndrome of adrenal insufficiency, and its cutaneous manifestations can include diffuse, gray dyspigmentation of the skin, mucosa, skin folds, and scar tissue. This skin discoloration is distinguished from drug-related causes by a constellation of abnormal serum laboratory test results, including hyponatremia, hyperkalemia, low serum cortisol levels, and an inappropriate response to a corticotrophin stimulation test.

Alternatively, hemochromatosis and Wilson disease induce a generalized, blue-gray metallic skin dyspigmentation; when the family history and other systemic involvement is unknown, findings that include elevated ferritin and trans -ferritin saturation levels or low serum copper or ceruloplasmin levels can help confirm these diagnoses.

Jaundice occurs when serum bilirubin levels are greater than 3 mg/dL; abnormally elevated serum bilirubin levels can help distinguish yellow dyspigmentation of the skin, conjunctiva, sclera, and oral mucosa from the discoloration sometimes induced by the antimalarial drugs mepacrine and quinacrine.

Normal thyroid function test results help eliminate hypothyroidism as a potential etiology of generalized yellow dyschromia.



In most acquired hyperpigmentation disorders, a uniform increase in melanin and/or chromophores can be seen upon histologic examination. A biopsy may not always be useful in differentiating drug-induced dyschromia from that of other causes. One exception is in the case of heavy metals, in which histological evidence can be helpful to identify metal deposition or unusual pigments within the dermis or dermal histiocytes.


Histologic Findings

The histologic findings of several forms of drug-induced pigmentation have been reported. The patterns of histologic abnormalities are often drug specific and have been described as hyperpigmentation of the basal cell layer, pigment incontinence within the dermis, and accumulation of pigment-laden macrophages around blood vessels and eccrine glands. The pigment within macrophages may be positive for the Fontana-Masson stain, indicating the presence of melanin, or may be positive for Perls Prussian blue stain, indicating the presence of iron; on occasion, both results may be positive with both stains.

Minocycline type I reactions demonstrate pigment-laden macrophages within the dermis or scar that are only positive with Perls staining. Minocycline type II reactions demonstrate pigment-laden macrophages around blood vessels and eccrine glands that stain with both Fontana-Masson and Perls stains, indicating the presence of both melanin and iron. Minocycline type III reactions have been characterized by the presence of increased epidermal basal cell layer melanin pigmentation.

Amiodarone pigmentation is a result of a form of photodistributed lipofuscinosis with accumulation of lysosomal laminated bodies within macrophages. These granules within macrophages stain positively with periodic acid-Schiff stain.

Phenothiazine pigmentation results from the accumulation of pigment-laden macrophages around superficial blood vessels. These macrophages stain with Fontana-Masson stain, but not Perls stain.

Chemotherapeutic agent–induced pigmentation may result from interface dermatitis, resulting in incontinence of pigment.

Antimalarial pigmentation demonstrates pigment granules extracellularly and within dermal macrophages that stain for hemosiderin, melanin, or both.