Cutaneous hyperpigmentation induced by amiodarone hydrochloride

doi:10.1016/S0190-9622(85)70079-5

Journal of the American Academy of Dermatology

Volume 12, Issue 3, March 1985, Pages 563-566

https://doi.org/10.1016/S0190-9622(85)70079-5 Get rights and content

Amiodarone (Cordarone) is an iodinated compound widely used in the treatment of cardiac arrhythmias for more than a decade. A patient who developed a persistent blue-gray skin pigmentation of the light-exposed areas following long-term amiodarone hydrochloride administration is reported. The cutaneous signs and the ultrastructural findings are described. This rare iatrogenic hyperpigmentation is peculiarly due to lipofuscin and not melanin deposits. Its pathogenesis may be related to the basic action of the drug on the lysosome and to the extra phototoxic-induced lysosomal damage, which accounts for the specific location of the hyperpigmentation over the light-exposed areas.

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Invisible dermatoses: clues and pitfalls to diagnosis
2018, Diagnostic Histopathology
Citation Excerpt :
Pigmentary disorders include silver nitrate deposits, where small blackish granules are detectable in the apex of the horny layer or tattoos where pigment granules may not be easily identifiable among the collagen fibres of the dermis. In argyria,22 rheumatoid arthritis,23 minocycline24 and amiodarone hyperpigmentation,25 yellow-brownish granules can be observed in the periadnexal area in correspondence to the reticular fibres or at an intra-macrophagic site. Dermatoses with anomalies of the elastic tissue are not meaningful at H&E.
The phrase “invisible dermatoses” has been used in two different contexts: 1) Invisible dermatoses to the clinician, i.e., skin diseases with no significant clinical features, 2) invisible dermatoses to the pathologist, i.e., clinical evident skin diseases that show subtle or hidden histological features resembling normal skin. The list of such diseases, originally comprising only few entities, has been gradually expanded over decades and now is a large one. This paper will focus on entities that fall into this category of subtle or “invisible” dermatoses histopathologically and offers to the dermatopathologist a strategy for their diagnosis, based mainly on proper awareness, recognition of subtle features, liberal use of special stains, immunofluorescence and immunohistochemistry and proper clinicopathologic correlation. The presentation of a series of “invisible dermatoses” will hopefully familiarize the reader with the diagnostic problems and pitfalls associated with and unique to the interpretation of biopsies from this category of dermatoses.
Cutaneous deposits
2009, Weedon's Skin Pathology: Third Edition
Photoinduced dermal pigmentation in patients talcing tricyclic antidepressants: Histology, electron microscopy, and energy dispersive spectroscopy
1999, Journal of the American Academy of Dermatology
Two patients had been taking long-term tricyclic antidepressant therapy. Each developed a blue to slate-gray hyperpigmentation in sun-exposed areas. On histologic examination there were refractile golden brown granules free in the dermis along collagen bundles. Similar pigment was present in macrophages and along the basement membrane zone. The granules stained for melanin, but not for iron, and were bleached by the permanganate method. Electron microscopy showed varying size and shaped electron-dense granules within lysosomes and free in the dermis, which, in unstained sections, showed a less dense peripheral halo. This peripheral halo was also evident on light microscopy. Energy dispersive spectroscopy showed these granules to be rich in copper and sulfur (elements present in tyrosinase and pheomelanin, respectively). We believe that this represents a drug-melanosome complex, which is most likely caused by chronic photoactivation. (J Am Acad Dermatol 1999;40:290-3.)
Imipramine-induced hyperpigmentation: Four cases and a review of the literature
1999, Journal of the American Academy of Dermatology
Background: Hyperpigmentation is a side effect of several medications, including amiodarone, bleomycin, chlorpromazine, and minocycline. Objective: The purpose of this study is to describe the clinical and light microscopic findings in 4 patients with imipramine-induced hyperpigmentation and to better understand its origin. Methods: All 4 patients underwent a skin biopsy for light microscopy. In 1 patient, a biopsy specimen was obtained for electron microscopy. Tissue from patient 1 was analyzed with a mass spectrophotometer, and energy-dispersive x-ray analysis was performed on tissue from patients 1 and 2. Results: All 4 women had been taking imipramine for at least 2 years. Hyperpigmentation occurred in a photodistribution on the face, arms, and backs of the hands. Light microscopy in all cases demonstrated golden-brown granules in the superficial dermis, which were strongly positive for Fontana-Masson stain. Electron microscopy demonstrated areas of electron-dense inclusion bodies within macrophages, which were distinct from melanosomes. Mass spectrophotometric and energy-dispersive x-ray analysis of the electron-dense bodies showed the presence of sulfur atoms, and no peak corresponding to that expected for imipramine was found. A peak closely corresponding to phaeomelanin, a sulfur-containing compound, was found. Conclusion: Hyperpigmentation is a side effect of long-term imipramine use. It may result from the deposition of melanin in an unusual form. The melanin pigment is possibly complexed with a metabolite of imipramine, and does not represent the deposition of imipramine in its native form. (J Am Acad Dermatol 1999;40:159-66.)
A general overview of amiodarone toxicity: Its prevention, detection, and management
1989, Progress in Cardiovascular Diseases
Although amiodarone is a highly effective antiarrhythmic agent, it has a high incidence of side effects, some of which can be serious or even lethal. With close monitoring, side effects can be found in essentially all patients, but fortunately most of these are mild and well tolerated. Furthermore, many will respond to dosage reduction in a relatively short period of time, ie, days to weeks, which is remarkable considering the long period of time amiodarone has been shown to persist in tissues. There is reasonable evidence that toxicity, particularly the early toxic manifestations with large loading dosages, can be favorably modified by reducing the dosage. Similarly, reducing the maintenance dosage will, in most instances, reduce or eliminate most toxic manifestations. The mechanisms of toxic effects are uncertain, but suggestive evidence exists for and against both an immunologic reaction and an intracellular lysosomal lipoidosis.
Principles of use of amiodarone should include individualizing administration of dosages for each patient due to the unusual pharmacokinetic properties of this drug and continuous long-term attempts at using the lowest effective dosage. There are no definite tests that predict amiodarone efficacy or toxicity, but the serum level can be used as a rough guide of absorption and distribution in the attempt to minimize the maintenance dosage. No guidelines regarding screening tests for toxicity can be made at this time since great variability in these tests has been reported, and no evidence exists for their benefit in preventing adverse effects to amiodarone. However, follow-up testing at the intervals noted in the package insert are reasonable and important. The possibility of interactions with drugs already reported and with others not yet reported should always be kept in mind, and appropriate monitoring for clinical evidence of toxicity due to the concomitantly used drugs should be undertaken.
Amiodarone can have a tremendous beneficial effect in the proper circumstances, but it is a drug that should command utmost respect because of its side effects and requires constant vigilance from any physician wishing to use it.
Chemical and pharmacologic agents that cause hyperpigmentation or hypopigmentation of the skin
1988, Dermatologic Clinics
A wide variety of chemicals are capable of altering skin color. Those capable of causing hyperpigmentation include many cancer chemotherapeutic agents, antibiotics, metals, hormones, neuroleptics, cardiac medicines, and dyes. Hypopigmentation is most commonly caused by catechols, phenols, and sulfhydryl compounds. This article lists the chemicals and the postulated mechanisms by which they alter skin color and describes the histopathologic changes that occur.

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Case reportsCutaneous hyperpigmentation induced by amiodarone hydrochloride

Étude clinique d'un nouvelle médication anti-angoreuse

Acta Cardiol (Brux)

Etude clinique de l'amiodarone daps les troubles du rhythme cardiaque

Presse Med

Iododerma caused by amiodarone

Arch Dermatol

Amiodarone et dépots cutanès: Étude clinique et histologique

Ann Dermatol Syphiligr

Amiodarone-pigmentierung eine seltene, aber tipische medikament-nebenwirkung

Hautarzt

A peculiar cutaneous pigmentation from Cordarone

Dermatologica

Case reports
Cutaneous hyperpigmentation induced by amiodarone hydrochloride