J Am Board Fam Med: first published as 10.3122/jabfm.2019.04.180212 on 12 July 2019. Downloaded from CLINICAL REVIEW Drug-Induced Hyperpigmentation: Review and Case Series Rosa M. Gime´nez García, MD, and Sergio Carrasco Molina, MIR Background: Hyperpigmentation is a common dermatologic problem that may have substantial impact on the patient, since it affects the appearance and quality of life, and may influence treatment adher- ence. There are few studies of drug-induced hyperpigmentation. Methods: We studied drug-induced hyperpigmentation in patients attending an outpatient dermatol- ogy clinic in the Western Area of Valladolid (Spain) from August 1, 2017 to April 20, 2018. Results: The incidence of drug-induced hyperpigmentation was 1.31% in patients attending a first dermatology consultation in the study period. Of the 16 patients, 8 were taking more than 1 drug. The most frequent drugs identified were nonsteroidal anti-inflammatory agents (25%), antihypertensive agents (18.75%), antimalarials (12.5%), antibiotics, antineoplastic agents, psychoactive agents, simva- statin, allopurinol, amiodarone and mucolytic (6.25% each). Hyperpigmentation was found in the mu- cosa in 25% of patients and in photograph-exposed areas in 37.5%. Discussion: Diagnosing drug-induced hyperpigmentation is a dermatologic challenge. A differential diagnosis with hyperpigmentation caused by endocrine and metabolic disorders, the most closely-re- lated disorders to drug-induced hyperpigmentation, and with hyperpigmentation of idiopathic origin, should be conducted. Drug-induced hyperpigmentation is a relatively frequent reason for consultation, especially in polypharmacy patients. The sample may have been biased as many patients receiving treat- ments frequently associated with drug-induced hyperpigmentation, such as antineoplastic drugs, are copyright. diagnosed and treated by other specialties, such as oncologists. Conclusion: Family physicians and specialists should consider drugs as a cause of hyperpigmenta- tion to facilitate the correct diagnosis and treatment. (J Am Board Fam Med 2019;32:628–638.) Keywords: Dermatology, Hyperpigmentation, Pharmacology, Practice Management, Spain Hyperpigmentation is a common dermatologic to dermal deposition of endogenous or exogenous http://www.jabfm.org/ problem that may have substantial impact on the pigments such as hemosiderin, iron or heavy met- patient, since it affects the appearance and quality als. Hyperpigmentation is a frequent reason for of life. Hyperpigmentation is defined as the dark- consultation, particularly in patients with darker ening of the skin’s natural color, usually due to an skin.1 increase in melanin deposition (hypermelanosis) in The color of human skin is mainly determined the epidermis or dermis, an increase in chro- by 2 types of melanin; eumelanin and pheomelanin. on 24 September 2021 by guest. Protected mophores of nonmelanic origin (hyperchromia), or Other important determinants of skin color are the number of blood capillaries it contains, the chro- mophores it may possess, such as carotenoids or lycopenes, and the collagen content of the dermis.2 This article was externally peer reviewed. Submitted 26 July 2018; revised 24 February 2019; ac- The melanocytes, located in the epidermal basal cepted 26 February 2019. layer, produce melanin by biosynthesis in the or- From the Department of Medicine, Dermatology and Tox- icology, Faculty of Medicine, Valladolid, Spain (RMGG); De- ganelles called melanosomes, which are transported partment of Dermatology, Hospital Universitario Rio to the periphery and transferred, thanks to their Hortega, Valladolid, Spain (SCM). Funding: none. dendritic extensions, from the melanocytes to the Conflict of interest: none declared. surrounding keratinocytes. Each melanocyte inter- Corresponding author: Rosa Gimenez Garcia, MD, Calle Carabela 115, Boecillo, 47151 Valladolid, Spain (E-Mail: acts with more or less 36 keratinocytes, in what is [email protected]͒. known as the melano-epidermal unit.2 628 JABFM July–August 2019 Vol. 32 No. 4 http://www.jabfm.org J Am Board Fam Med: first published as 10.3122/jabfm.2019.04.180212 on 12 July 2019. Downloaded from Hypermelanosis in the epidermis is caused by an especially when the chronology between taking the increase in melanin in the basal and suprabasal drug and the onset of hyperpigmentation is un- layer of the skin associated with a normal or ele- known. The true incidence of drug-induced hyper- vated amount of melanocytes. Dermal hypermela- pigmentation is very difficult to estimate because nosis may be due to various mechanisms, such as not all cases are recorded or reported for pharma- the transfer of melanin from the epidermis to the cological study, and there are no large-scale pro- dermis and its accumulation within the mel- spective studies. The aims of this study were to anophages (pigmentary incontinence), and is com- review drug-induced hyperpigmentation, to carry monly observed in inflammatory skin diseases af- out a study of patients with drug-induced hyper- fecting the basal layer and/or the dermal-epidermal pigmentation attending a dermatology clinic for junction. Another cause is dermal deposition of the first time, and to summarize the drugs known to endogenous and exogenous pigments, such as he- cause hyperpigmentation.4,11 mosiderin or iron, or a local or systemic exposure to heavy metals (silver, gold, mercury). Metals such Review as iron can stimulate melanogenesis, as observed in Antibiotics patients with hemochromatosis.3 Tetracycline-induced hyperpigmentation is mainly Drug-induced hyperpigmentation is estimated due to minocycline and, less frequently, doxycy- to account for 10% to 20% of cases of acquired cline or other first-generation tetracyclines. Mino- hyperpigmentation,4 although these figures are cycline-induced hyperpigmentation may occur in probably highly speculative, as most cases are idio- up to 15% of patients, especially those receiving pathic, especially in elderly patients. The incidence prolonged treatment. Three types of hyperpigmen- of drug-induced hyperpigmentation varies accord- tation induced by minocycline have been described: ing to the drug involved, ranging from isolated hyperpigmentation type 1 (blue-black hyperpig- cases to 25% of patients receiving a treatment.5 mentation in the site of previous inflammation or Some drugs are associated with the development of scarring) produced by pigment granules, probably copyright. hyperpigmentation of the skin or mucous mem- iron chelates of minocycline; type 2 hyperpigmen- branes.4–6 tation (gray-blue hyperpigmentation that affects Clinically, the discoloration that appears on the normal skin, especially the legs) is probably due to skin is acquired and usually grows slowly and minocycline metabolites in the skin; type 3 hyper- spreads insidiously, worsening over months or pigmentation (dirty skin syndrome in areas exposed years after treatment initiation. Some topograph- to the sun) in which microscopic studies finds ical distributions are more characteristic of drug- higher amounts of melanin in the macrophages of http://www.jabfm.org/ induced hyperpigmentation, such as areas ex- the epidermis and dermis (Figure 1). This probably posed to the sun, and may include the mucous also applies to type-4 hyperpigmentation (hyper- membranes, especially the oral and conjunctive pigmentation of scars).11,12 membranes. Some characteristics of the distribu- Isolated cases of hyperpigmentation due to levo- tion are very suggestive of specific drugs, such as floxacin have been described, although in isolated the flagellated hyperpigmentation found when cases and long-term treatment regimens, or due to cytostatic treatments containing bleomycin are polymyxin, an antibiotic used primarily for resis- on 24 September 2021 by guest. Protected used.7 The color acquired due to hyperpigmen- tance against Gram-negative germs, or to tigecy- tation is not specific for drug-induced hyperpig- cline, a new glycylcycline antibiotic.13–16. mentation. However, drug-induced hyperpig- Overdoses of rifampicin may induce reddish hy- mentation frequently presents as an unusual perpigmentation,17 whereas isoniazid may some- purple, with color tones such as red-yellow (clo- times produce purplish hyperpigmentation associ- fazimine),8 or slate or blue-gray (psychotropic ated with pellagra.18 Dapsone may also trigger drugs, amiodarone, or metals).9,10 hyperpigmentation aggravated by the sun.19 The diagnosis of hyperpigmentation is compli- cated due to the lack of direct evidence or inade- Antihypertensives quate information. Many elderly patients are re- Despite their widespread use, very few cases of ceiving polypharmacy, making it more difficult to hyperpigmentation induced by antihypertensive associate a pigment change with a specific drug, drugs have been reported. doi: 10.3122/jabfm.2019.04.180212 Drug-Induced Hyperpigmentation 629 J Am Board Fam Med: first published as 10.3122/jabfm.2019.04.180212 on 12 July 2019. Downloaded from Figure 1. Minocycline induced facial Figure 2. Hyperpigmentation due to lercanidipine. hyperpygmentation. ropathic pain. Changes in hair color and curly hair Angiotensin II receptor antagonists block the have been described after use as have changes in binding of angiotensin II to its receptor subtype 1. nail pigmentation30,31 and 1 case of labial hyper- Increased use of these antihypertensive agents has pigmentation.32 led to more visits to pharmacovigilance centers, but Ten percent of patients taking phenytoin de- copyright.