Drug-Induced Pigmentation Workup
- Author: David F Butler, MD; Chief Editor: Dirk M Elston, MD more...
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.
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.
Halder RM, Nandedkar MA, Neal KW. Pigmentary disorders in ethnic skin. Dermatol Clin. 2003 Oct. 21(4):617-28, vii. [Medline].
Koranda FC. Antimalarials. J Am Acad Dermatol. 1981 Jun. 4(6):650-5. [Medline].
Bronner AK, Hood AF. Cutaneous complications of chemotherapeutic agents. J Am Acad Dermatol. 1983 Nov. 9(5):645-63. [Medline].
Fernandez-Obregon AC, Hogan KP, Bibro MK. Flagellate pigmentation from intrapleural bleomycin. A light microscopy and electron microscopy study. J Am Acad Dermatol. 1985 Sep. 13(3):464-8. [Medline].
Haas N, Vogt R, Sterry W. [Shiitake dermatitis: flagellate dermatitis after eating mushrooms]. Hautarzt. 2001 Feb. 52(2):132-5. [Medline].
Hrushesky WJ. Unusual pigmentary changes associated with 5-fluorouracil therapy. Cutis. 1980 Aug. 26(2):181-82. [Medline].
Ghosh, S. K., D. Bandyopadhyay, L. Ghoshal, and S. Basu. Letter: Docetaxel-induced supravenous serpentine dermatitis. Dermatology Online Journal. 2011 Nov 15. 17:(11):16.
Geddes ER, Cohen PR. Antineoplastic agent-associated serpentine supravenous hyperpigmentation: superficial venous system hyperpigmentation following intravenous chemotherapy. South Med J. 2010 Mar. 103(3):231-5. [Medline].
Schallier D, Decoster L, de Greve J. Pemetrexed-induced hyperpigmentation of the skin. Anticancer Res. 2011 May. 31(5):1753-5. [Medline].
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 2005. 16:1425-33.
Heidary N, Naik H, Burgin S. Chemotherapeutic agents and the skin: An update. J Am Acad Dermatol. 2008 Apr. 58(4):545-70.
Bleehen SS, Gould DJ, Harrington CI, Durrant TE, Slater DN, Underwood JC. Occupational argyria; light and electron microscopic studies and X-ray microanalysis. Br J Dermatol. 1981 Jan. 104(1):19-26. [Medline].
Tanita Y, Kato T, Hanada K, Tagami H. Blue macules of localized argyria caused by implanted acupuncture needles. Electron microscopy and roentgenographic microanalysis of deposited metal. Arch Dermatol. 1985 Dec. 121(12):1550-2. [Medline].
White MI. Localized argyria caused by silver earrings. Br J Dermatol. 1997 Jun. 136(6):980. [Medline].
Cremer B, Czarnetzki BM. [Skin discolorations under gold jewelry]. Dtsch Med Wochenschr. 1992 Apr 3. 117(14):558. [Medline].
Eisen D, Hakim MD. Minocycline-induced pigmentation. Incidence, prevention and management. Drug Saf. 1998 Jun. 18(6):431-40. [Medline].
McGrae JD Jr, Zelickson AS. Skin pigmentation secondary to minocycline therapy. Arch Dermatol. 1980 Nov. 116(11):1262-5. [Medline].
Pepine M, Flowers FP, Ramos-Caro FA. Extensive cutaneous hyperpigmentation caused by minocycline. J Am Acad Dermatol. 1993 Feb. 28(2 Pt 2):292-5. [Medline].
Simons JJ, Morales A. Minocycline and generalized cutaneous pigmentation. J Am Acad Dermatol. 1980 Sep. 3(3):244-7. [Medline].
Fraunfelder FT, Randall JA. Minocycline-induced scleral pigmentation. Ophthalmology. 1997 Jun. 104(6):936-8. [Medline].
Green D, Friedman KJ. Treatment of minocycline-induced cutaneous pigmentation with the Q-switched Alexandrite laser and a review of the literature. J Am Acad Dermatol. 2001 Feb. 44(2 Suppl):342-7. [Medline].
Alster TS, Gupta SN. Minocycline-induced hyperpigmentation treated with a 755-nm Q-switched alexandrite laser. Dermatol Surg. 2004 Sep;. 30(9):1201-4.
Greve B, Schonermark MP, Raulin C. Minocycline-induced hyperpigmentation: Treatment with the Q-switched nd:YAG laser. Lasers Surg Med. 1998. 22(4):223-7.
Wilde JL, English JC,3rd, Finley EM. Minocycline-induced hyperpigmentation. treatment with the neodymium:YAG laser. Arch Dermatol. 1997 Nov. 133(11):1344-6.
Wood B, Munro CS, Bilsland D. Treatment of minocycline-induced pigmentation with the neodymium-yag laser. Br J Dermatol. 1998 Sep;139(3):562.
Kounis NG, Frangides C, Papadaki PJ, Zavras GM, Goudevenos J. Dose-dependent appearance and disappearance of amiodarone-induced skin pigmentation. Clin Cardiol. 1996 Jul. 19(7):592-4. [Medline].
Trimble JW, Mendelson DS, Fetter BF, Ingram P, Gallagher JJ, Shelburne JD. Cutaneous pigmentation secondary to amiodarone therapy. Arch Dermatol. 1983 Nov. 119(11):914-8. [Medline].
Ward HA, Russo GG, Shrum J. Cutaneous manifestations of antiretroviral therapy. J Am Acad Dermatol. 2002 Feb. 46(2):284-93. [Medline].
Shirasaka T, Tadokoro T, Yamamoto Y, Fukutake K, Kato Y, Odawara T, et al. Investigation of emtricitabine-associated skin pigmentation and safety in HIV-1-infected Japanese patients. J Infect Chemother. 2011 Oct. 17(5):602-8. [Medline].
Job CK, Yoder L, Jacobson RR, Hastings RC. Skin pigmentation from clofazimine therapy in leprosy patients: a reappraisal. J Am Acad Dermatol. 1990 Aug. 23(2 Pt 1):236-41. [Medline].
MacMorran WS, Krahn LE. Adverse cutaneous reactions to psychotropic drugs. Psychosomatics. 1997 Sep-Oct. 38(5):413-22. [Medline].
Wolf ME, Richer S, Berk MA, Mosnaim AD. Cutaneous and ocular changes associated with the use of chlorpromazine. Int J Clin Pharmacol Ther Toxicol. 1993 Aug. 31(8):365-7. [Medline].
Bloom D, Krishnan B, Thavundayil JX, Lal S. Resolution of chlorpromazine-induced cutaneous pigmentation following substitution with levomepromazine or other neuroleptics. Acta Psychiatr Scand. 1993 Mar. 87(3):223-4. [Medline].
Lal S, Bloom D, Silver B, Desjardins B, Krishnan B, Thavundayil J, et al. Replacement of chlorpromazine with other neuroleptics: effect on abnormal skin pigmentation and ocular changes. J Psychiatry Neurosci. 1993 Jul. 18(4):173-7. [Medline].
Ming ME, Bhawan J, Stefanato CM, McCalmont TH, Cohen LM. Imipramine-induced hyperpigmentation: four cases and a review of the literature. J Am Acad Dermatol. 1999 Feb. 40(2 Pt 1):159-66. [Medline].
Narurkar V, Smoller BR, Hu CH, Bauer EA. Desipramine-induced blue-gray photosensitive pigmentation. Arch Dermatol. 1993 Apr. 129(4):474-6. [Medline].
Sicari MC, Lebwohl M, Baral J, Wexler P, Gordon RE, Phelps RG. Photoinduced dermal pigmentation in patients taking tricyclic antidepressants: histology, electron microscopy, and energy dispersive spectroscopy. J Am Acad Dermatol. 1999 Feb. 40(2 Pt 2):290-3. [Medline].
Atkin DH, Fitzpatrick RE. Laser treatment of imipramine-induced hyperpigmentation. J Am Acad Dermatol. 2000 Jul. 43(1 Pt 1):77-80. [Medline].
Garin Shkolnik T, Feuerman H, Didkovsky E, Kaplan I, Bergman R, Pavlovsky L, et al. Blue-gray mucocutaneous discoloration: a new adverse effect of ezogabine. JAMA Dermatol. 2014 Sep 1. 150(9):984-9. [Medline].
Baker H. Adverse cutaneous reaction to oral contraceptives. Br J Dermatol. 1969 Dec. 81(12):946-9. [Medline].
Blomberg M, Zachariae CO, Grønhøj F. Hyperpigmentation of the face following adalimumab treatment. Acta Derm Venereol. 2009. 89(5):546-7. [Medline].
Kramer KE, Lopez A, Stefanato CM, Phillips TJ. Exogenous ochronosis. J Am Acad Dermatol. 2000 May. 42(5 Pt 2):869-71. [Medline].
Chien KH, Lu DW, Chen JT. Extensive facial skin pigmentation after latanoprost treatment. Cutan Ocul Toxicol. 2009. 28(4):185-7. [Medline].
Sharpe ED, Reynolds AC, Skuta GL, Jenkins JN, Stewart WC. The clinical impact and incidence of periocular pigmentation associated with either latanoprost or bimatoprost therapy. Curr Eye Res. 2007 Dec. 32(12):1037-43. [Medline].
Li CC, Malik SM, Blaeser BF, Dehni WJ, Kabani SP, Boyle N, et al. Mucosal Pigmentation Caused by Imatinib: Report of Three Cases. Head Neck Pathol. 2011 Dec 31. [Medline].
Aleem A. Hypopigmentation of the skin due to imatinib mesylate in patients with chronic myeloid leukemia. Hematol Oncol Stem Cell Ther. 2009;2(2):358-61.
Alexandrescu DT, Dasanu CA, Farzanmehr H, Kauffman L. Persistent cutaneous hyperpigmentation after tyrosine kinase inhibition with imatinib for GIST. Dermatol Online J. 2008 Jul 15;14(7):7.:
Hemesath TJ, Price ER, Takemoto C, Badalian T, Fisher DE. MAP kinase links the transcription factor microphthalmia to c-kit signalling in melanocytes. Nature. 1998 Jan 15;391(6664):298-301.
Arya V, Grzybowski J, Schwartz RA. Carotenemia. Cutis. 2003 Jun. 71(6):441-2, 448. [Medline].
Friedman SJ, Butler DF, Pittelkow MR. Perilesional linear atrophy and hypopigmentation after intralesional corticosteroid therapy. Report of two cases and review of the literature. J Am Acad Dermatol. 1988 Sep. 19(3):537-41. [Medline].
Vine K, Meulener M, Shieh S, Silverberg NB. Vitiliginous lesions induced by amyl nitrite exposure. Cutis. 2013 Mar. 91(3):129-36. [Medline].
McKee PH, Calonje E, Granter SR. Cutaneous adverse reactions to drugs and effects of physical agents. Pathology of the Skin with Clinical Correlations. 3rd ed. London, England: Elsevier; 2005. Vol 1: 638-42.
Trout CR, Levine N, Chang MW. Disorders of hyperpigmentation. Bolognia JL, Jorizzo JL, Rapini RP, eds. Dermatology. St. Louis, Mo: Mosby; 2003. Vol 2: 975-1006.