Minocycline-induced hyperpigmentation

Journal of Family Practice, August, 1995 by Ping-Hsin Hung, James B. Caldwell, William D. James

A 70-year-old man developed hyperpigmentation of his forearms, hands, fingernails, sclerae, ears, and teeth after 9 years of therapy with minocycline for acne rosacea. Minocycline is widely used in the treatment of acne vulgaris and uncommonly produces the side effect of hyperpigmentation. This effect does not appear to be dose-dependent and usually resolves within months to years after discontinuation of therapy. Discoloration of adult teeth, however, is generally permanent.

Key words. Minocycline; hyperpigmentation; pigmentation; adverse effects; side effects. (J Fam Pract 1995; 40:183-185)

Adverse effects from minocycline hydrochloride are uncommon, and there are few reported cases of hyperpigmentation as a side effect of its use. The cutaneous hyperpigmentation usually resolves after cessation of the drug; however, tooth discoloration generally remains. Patients should be cautioned about this possible side effect, and the minocycline discontinued if hyperpigmentation develops.

Case Report

A 70-year-old white man presented with a 5-year history of progressive blue-gray pigmentation of his forearms, hands, fingernails, sclerae, ears, and teeth (Figure 1). He had been treated over the previous 9 years at another institution with minocycline 100 mg by mouth twice a day for a 20-year history of acne rosacea. The total dose he received was approximately 657 g.

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His medical history included chronic obstructive lung disease, coronary artery disease, benign prostatic hypertrophy, glaucoma, and macular degeneration. His medications included theophylline, prednisone, inhaled beclomethasone dipropionate and metaproterenol sulfate, verapamil hydrochloride, oxybutynin chloride, ophthalmic dipivefrin hydrochloride, and topical metronidazole.

A biopsy of the dorsum of his hand revealed a normal epidermis with hyperpigmentation of the basal layer. Dark-brown pigment granules were seen both within macrophages and free in the dermis (Figures 2 and 3).

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Since discontinuation of the minocycline in October 1992, there has been gradual resolution of the cutaneous pigment but no significant change in the discoloration of his teeth.

Discussion

Tetracyclines have a broad spectrum of activity against gram-positive and gram-negative organisms and are widely used to treat chlamydial, mycoplasmal, and rickettsial infections.(1)

Tetracyclines are known to chelate divalent and trivalent cations. Minocycline, a second-generation tetracycline, differs from the other tetracyclines in that it is completely absorbed from the gastrointestinal tract even when administered with dairy products. Maximum concentrations are reached within 2 to 3 hours, and its half-life is approximately 16 hours. Penetration of minocycline into tissues is excellent because it is the most lipophilic of the tetracyclines. This accounts for its high concentration in the brain, saliva, thyroid, lung, liver, reproductive organs, skin, and bones, and for its ability to cross the placenta and be excreted in breast milk.(2)

Since it was first introduced in 1967, minocycline has been generally well tolerated, and is widely used in the long-term treatment of acne vulgaris, particularly in cases unresponsive to other tetracyclines. Its most common side effect, which appears to be related to both dose and frequency of administration, is gastrointestinal, manifested as abdominal discomfort, nausea, vomiting, or diarrhea. Minocycline rarely causes photosensitivity or an exaggerated sunburn reaction on exposure to sunlight. Elevated liver enzyme levels or, rarely, hepatitis may develop, especially in patients receiving large doses, and uremia may be aggravated in patients with renal disease. Vestibular toxicity, with symptoms of vertigo or dizziness, generally resolves after discontinuation. Long-term therapy may produce changes in the peripheral blood, including neutropenia, hemolytic anemia, and thrombocytopenia. Periodic laboratory evaluations of hematopoietic, renal, and hepatic functions should be performed to monitor for any changes. The only known interaction between minocycline and this patient's other medications is with theophylline. Theophylline's serum concentration, and therefore its toxic effects, may be increased by tetracyclines. Among this patient's medications, there are no interactions known to cause hyperpigmentation.

Minocycline-induced hyperpigmentation of the skin was first reported in 1978.(3) Since then, scattered reports have documented other cases of skin darkening(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14) as well as pigmentation of conjunctival cysts,(15)(16) sclerae,(8)(10)(14) gingiva secondary to underlying pigmented bone,(11) teeth,(8)(17) nails,(8)(10) skeleton,(8) and thyroid.(18)(19)(20) Black galactorrhea has also been reported.(21)

There are three basic types of skin pigmentation caused by minocycline. The first is a blue-black pigmentation localized to areas of scarring or previous sites of inflammation. This pigment, found within dermal macrophages, stains positive for iron, and is found by electron microscopy in nonmembrane-bound granules.(22) The second type, a muddy-looking brown color on sun-exposed areas, is thought to be caused by increased epidermal melanization.(22) The third is a localized blue-gray pigment in areas of previously normal skin, preferentially affecting the lower legs and areas exposed to sunlight. These pigments are found membrane-bound or free within dermal histiocytes. Iron, melanin, or a minocycline derivative chelated to iron or calcium may be the cause of this pigment, or this chelated compound may then be further oxidized by intralysosomal enzymes to produce a colored quinone.(9)