Diltiazem-Induced Hyperpigmentation

Tracy Kuykendall-Ivy, MD; Susannah Lambird Collier, MD; Sandra Marchese Johnson, MD

A healthy-appearing 66-year-old black woman trunk, and bilateral upper and lower extremities presented with a 5-year history of facial hyper- were unaffected. pigmentation that was unresponsive to topical The punch biopsy findings from a hyperpig- sunscreen, hydroquinone, tretinoin, and azelaic mented papule on the right temple revealed com- acid. Her medications included extended- pact hyperkeratosis and follicular dilation. In release diltiazem for hypertension for the past addition, there was a dense inflammatory infiltrate 7 years, rofecoxib for arthritis, and pantoprazole along the dermal-epidermal junction with abun- for esophagitis. On examination, the woman dis- dant dying keratinocytes (Figure 2). Pigment played hyperpigmented patches and papules incontinence was marked. There was an intense involving most of her face. The punch biopsy superficial to mid-dermal perivascular and perifol- findings from a hyperpigmented papule on the licular lymphocytic infiltrate. Laboratory findings, right temple revealed compact hyperkeratosis, including a wintrobe erythrocyte sedimentation follicular dilation, and dense inflammatory infil- rate, antinuclear antibody, anti-DNA, hepatitis trate along the dermal-epidermal junction with screen, Ro (SS-A), and La (SS-B), were all nega- abundant dying keratinocytes. Her diltiazem tive or within reference range. therapy was discontinued, which led to gradual Extended-release diltiazem was discontinued. Four resolution of her hyperpigmentation. months after discontinuation of the drug therapy, the Cutis. 2004;73:239-240. patient displayed lightening of the hyperpigmenta- tion and flattening of the papules (Figure 1B).

Case Report Comment A healthy-appearing 66-year-old black woman pre- When a patient presents with hyperpigmentation sented with a 5-year history of facial hyperpigmenta- of the face, many diagnoses may be suspected, tion. The patient presented to our clinic for a second including melasma, exogenous ochronosis, post- opinion and possible laser therapy. For 5 years, she inflammatory hyperpigmentation, drug-induced was under the care of a physician who treated her hyperpigmentation, erythema dyschromicum per- unsuccessfully with topical sunscreen, hydroquinone, stans, Riehl melanosis, acquired immunodeficiency tretinoin, and azelaic acid. Despite these therapies, syndrome, systemic lupus erythematosus, alkap- her pigmentation continued to progress. tonuria, macular amyloidosis, Addison disease, and Her medical history was significant for hyperten- hemochromatosis. When a lichenoid infiltrate or sion and osteoporosis. Her medications included interface dermatitis is present, a histologically extended-release diltiazem for hypertension for the different set of diagnoses should be considered previous 7 years, rofecoxib for arthritis, and panto- including actinic lichen planus, dermatomyositis, prazole for esophagitis. and lichenoid drug reactions (gold, antimalarials, On examination, the patient was healthy- penicillamine, thiazide diuretics, beta-blockers, appearing with Fitzpatrick skin type V with coalesc- angiotensin-converting enzyme inhibitors, and ing hyperpigmented patches and papules involving nonsteroidal anti-inflammatory drugs). We propose most of her face (Figure 1A). Her hands, neck, that extended-release diltiazem should be added to the list of lichenoid drug reactions, especially when Accepted for publication December 18, 2003. associated with intense hyperpigmentation. From the Department of Dermatology, University of Arkansas for Diltiazem hydrochloride is a widely used calcium Medical Sciences, Little Rock. channel–blocking agent for treatment of hyperten- The authors report no conflict of interest. sion and angina, especially among the black popula- Reprints: Sandra Marchese Johnson, MD, Department of Dermatology, University of Arkansas for Medical Sciences, tion. Diltiazem has been noted to cause serious CSC 124 A, Slot 576, 4301 W Markham, Little Rock, AR 72205 cutaneous manifestations such as toxic epidermal (e-mail: [email protected]). necrolysis, Stevens-Johnson syndrome, and erythema

VOLUME 73, APRIL 2004 239 Diltiazem-Induced Hyperpigmentation

A B

Figure 1. Hyperpigmented patches and papules on the face (A). Improvement following discontinuation of extended-release diltiazem (B).

Figure 2. A dense inflamma- tory infiltrate, abundant dying keratinocytes, and compact hyperkeratosis (H&E, original magnification 40).

multiforme.1 In a recent case report, extended- Extended-release diltiazem–induced hyperpig- release diltiazem was implicated histologically in mentation is the most likely diagnosis in our cur- causing facial hyperpigmentation in a black woman rent patient given the improvement of her facial with a lichenoid infiltrate.2 In that case, the woman color less than 6 months after discontinuation of was taking extended-release diltiazem for approxi- the drug. This reaction may be more common than mately 2 years before she noticed the hyperpigmen- once thought. tation. Scherschun et al3 also have described 4 patients, all African American with a mean age of REFERENCES 62 years, with photodistributed hyperpigmentation 1. Stern R, Khalsa JH. Cutaneous adverse reactions associated associated with extended-release diltiazem. The mean with calcium channel blockers. Arch Intern Med. duration of diltiazem administration prior to the 1989;149:829-832. development of hyperpigmentation was 8 months. 2. Chawla A, Goyal S. Diltiazem-induced hyperpigmentation Histopathologic examination in these cases also in an African American woman. J Am Acad Dermatol. showed lichenoid dermatitis with prominent pig- 2002;46:468-469. mentary incontinence. Discontinuation of dilti- 3. Scherschun L, Lee MW, Lim HW. Diltiazem-associated azem therapy resulted in the gradual resolution of photodistribution hyperpigmentation: a review of 4 cases. the hyperpigmentation in these cases.2,3 Arch Dermatol. 2001;137:179-182.

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