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Reversibility of Blue-Gray Cutaneous Discoloration From Amiodarone

1991; Elsevier BV; Volume: 66; Issue: 7 Linguagem: Inglês

10.1016/s0025-6196(12)62085-0

1942-5546

Joseph L. Blackshear, Henry W. Randle,

Photodynamic Therapy Research Studies

A 45-year-old man had severe blue-gray cutaneous discoloration during amiodarone therapy for atrial fibrillation. Therefore, this drug regimen was discontinued, and long-term anticoagulation and digoxin therapy were used. The patient was advised to avoid exposure of his skin to sunlight, and a bleaching agent was prescribed. After 18 months of follow-up, the blue-gray hyperpigmentation had diminished. Although photosensitivity reactions from amiodarone occur in more than 50% of patients, blue-gray cutaneous discoloration occurs in less than 10% of patients on prolonged therapy with amiodarone. The presence of high concentrations of iodine, detected by electron probe analysis, suggests that the cutaneous deposits are amiodarone itself or a metabolite. The slow rate of elimination of amiodarone and a high uptake by fat-associated tissues may explain the delayed disappearance of cutaneous photosensitivity and late resolution of the blue-gray discoloration. Our current case supports the reversibility of these adverse effects on long-term follow-up. A 45-year-old man had severe blue-gray cutaneous discoloration during amiodarone therapy for atrial fibrillation. Therefore, this drug regimen was discontinued, and long-term anticoagulation and digoxin therapy were used. The patient was advised to avoid exposure of his skin to sunlight, and a bleaching agent was prescribed. After 18 months of follow-up, the blue-gray hyperpigmentation had diminished. Although photosensitivity reactions from amiodarone occur in more than 50% of patients, blue-gray cutaneous discoloration occurs in less than 10% of patients on prolonged therapy with amiodarone. The presence of high concentrations of iodine, detected by electron probe analysis, suggests that the cutaneous deposits are amiodarone itself or a metabolite. The slow rate of elimination of amiodarone and a high uptake by fat-associated tissues may explain the delayed disappearance of cutaneous photosensitivity and late resolution of the blue-gray discoloration. Our current case supports the reversibility of these adverse effects on long-term follow-up. Blue-gray cutaneous pigmentation is among the many toxic effects of prolonged therapy with amiodarone hydrochloride.1McKenna WJ Rowland E Krikler DM Amiodarone: the experience of the past decade.Br Med J. 1983; 287: 1654-1656Crossref PubMed Scopus (30) Google Scholar, 2Raeder EA Podrid PJ Lown B Side effects and complications of amiodarone therapy.Am Heart J. 1985; 109: 975-983Abstract Full Text PDF PubMed Scopus (181) Google Scholar, 3Vrobel TR Miller PE Mostow ND Rakita L A general overview of amiodarone toxicity: its prevention, detection, and management.Prog Cardiovasc Dis. 1989; 31: 393-426Abstract Full Text PDF PubMed Scopus (101) Google Scholar Unlike amiodarone-induced corneal deposits, which usually resolve completely 6 to 12 months after cessation of use of the drug, the reversibility of amiodarone-induced cutaneous discoloration is uncertain.1McKenna WJ Rowland E Krikler DM Amiodarone: the experience of the past decade.Br Med J. 1983; 287: 1654-1656Crossref PubMed Scopus (30) Google Scholar, 2Raeder EA Podrid PJ Lown B Side effects and complications of amiodarone therapy.Am Heart J. 1985; 109: 975-983Abstract Full Text PDF PubMed Scopus (181) Google Scholar, 3Vrobel TR Miller PE Mostow ND Rakita L A general overview of amiodarone toxicity: its prevention, detection, and management.Prog Cardiovasc Dis. 1989; 31: 393-426Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 4Walter JF Bradner H Curtis GP Amiodarone photosensitivity.Arch Dermatol. 1984; 120: 1591-1594Crossref PubMed Scopus (27) Google Scholar, 5Miller RAW McDonald ATJ Dermal lipofuscinosis associated with amiodarone therapy: report of a case.Arch Dermatol. 1984; 120: 646-649Crossref PubMed Scopus (28) Google Scholar, 6Ferguson J Addo HA Jones S Johnson BE Frain-Bell W A study of cutaneous photosensitivity induced by amiodarone.Br J Dermatol. 1985; 113: 537-549Crossref PubMed Scopus (58) Google Scholar In this report, we describe a case of discoloration from long-term amiodarone therapy, which abated 18 months after use of the medication had been discontinued. The reversibility of the hyperpigmentation is discussed in light of the current and prior reports and the unusual pharmacokinetics of amiodarone. In September 1988, a 45-year-old barber came to our institution because of facial discoloration. He had been well until 1980, when sudden development of dyspnea and rapid atrial fibrillation necessitated hospitalization. Digoxin and quinidine were prescribed. Because of gastrointestinal complaints, disopyramide was substituted for the quinidine. Cardioversion was performed, but atrial fibrillation recurred. The disopyramide regimen was discontinued, an intravenous load of procainamide hydrochloride was administered, and cardioversion to sinus rhythm was achieved. Several weeks later, atrial fibrillation recurred, and he was treated with digoxin and warfarin sodium. In June 1983, amiodarone therapy was begun at 1,000 mg/day for 1 week followed by 600 mg/day. In November 1983, the dosage was increased to 800 mg/day. At that time, he complained of photosensitivity and was advised to use a sunscreen. He underwent cardioversion to sinus rhythm in December 1983, and warfarin therapy was discontinued. During a 3-month period, the daily dose of amiodarone was tapered from 800 mg to 200 mg. In November 1984, atrial fibrillation again necessitated cardioversion. In January 1986, the patient had difficulty speaking and right hemiparesis, which resolved after 20 minutes. An electrocardiogram revealed sinus rhythm with premature beats. Anticoagulation was begun, and at dismissal his treatment regimen consisted of amiodarone (600 mg/day) and warfarin. Between January 1986 and September 1988, his amiodarone dosage was 600 mg/day. Blue-gray discoloration of the face and forearms was noted in early 1987. At the time of initial examination at our institution in September 1988, the patient was taking digoxin (0.25 mg/day), warfarin (5 mg/day), hydrochlorothiazide (50 mg/day), and amiodarone (600 mg/day). No symptoms of congestive heart failure were present. On physical examination, he had dramatic blue-brown and blue-gray discoloration of the face (Fig. 1 A and B), hands, and forearms. A grade 2 (on the basis of 1 to 6) basal systolic ejection murmur was noted. Echocardiography disclosed mild left ventricular and left atrial dilatation in association with normal systolic function. Mitral regurgitation was detected by Doppler echocardiography. Electrocardiographic and Holter monitoring revealed sinus rhythm and premature atrial complexes. Results of pulmonary function tests were normal. Corneal deposits were seen on slit-lamp examination. Skin biopsy specimens showed pigmentary incontinence in conjunction with focal vacuolar alteration and basal layer hyperpigmentation (Fig. 2). The patient was concerned about the effect of his appearance on his occupation. Because of his history of recurrent atrial fibrillation, multiple drug trials, manifest amiodarone toxicity, and a prior cerebral embolic event, we elected to abandon amiodarone therapy and to continue long-term oral anticoagulant and digoxin therapy. Since that time, he has been treated with digoxin (0.25 mg daily) and warfarin to maintain the prothrombin time at 1.5 to 1.7 times control. We assumed that the discoloration was phototoxic in origin. Because melanin was increased in the basal layer, the patient was treated with a bleaching cream (0.1 tretinoin, 5% hydroquinone, and 0.1% triamcinolone cream) applied twice daily plus a broad-spectrum sunscreen that included protection from sunlight in the ultraviolet A range. He used the bleaching agent for approximately 4 months without a dramatic change. During 18 months of follow-up, the discoloration gradually disappeared. Follow-up photographs were obtained in April 1990 (Fig. 1 C and D). His skin condition continued to improve, and he required no exceptional use of sunscreen for the Florida summer of 1990. Amiodarone-induced blue-gray cutaneous discoloration occurs in less than 10% of patients on long-term therapy with the drug.1McKenna WJ Rowland E Krikler DM Amiodarone: the experience of the past decade.Br Med J. 1983; 287: 1654-1656Crossref PubMed Scopus (30) Google Scholar, 2Raeder EA Podrid PJ Lown B Side effects and complications of amiodarone therapy.Am Heart J. 1985; 109: 975-983Abstract Full Text PDF PubMed Scopus (181) Google Scholar, 3Vrobel TR Miller PE Mostow ND Rakita L A general overview of amiodarone toxicity: its prevention, detection, and management.Prog Cardiovasc Dis. 1989; 31: 393-426Abstract Full Text PDF PubMed Scopus (101) Google Scholar, 4Walter JF Bradner H Curtis GP Amiodarone photosensitivity.Arch Dermatol. 1984; 120: 1591-1594Crossref PubMed Scopus (27) Google Scholar, 5Miller RAW McDonald ATJ Dermal lipofuscinosis associated with amiodarone therapy: report of a case.Arch Dermatol. 1984; 120: 646-649Crossref PubMed Scopus (28) Google Scholar, 6Ferguson J Addo HA Jones S Johnson BE Frain-Bell W A study of cutaneous photosensitivity induced by amiodarone.Br J Dermatol. 1985; 113: 537-549Crossref PubMed Scopus (58) Google Scholar Histologic section of affected skin has revealed yellow-brown pigment, chiefly in macrophages and fibroblasts. Histochemically, the pigment resembles lipofuscin;5Miller RAW McDonald ATJ Dermal lipofuscinosis associated with amiodarone therapy: report of a case.Arch Dermatol. 1984; 120: 646-649Crossref PubMed Scopus (28) Google Scholar, 6Ferguson J Addo HA Jones S Johnson BE Frain-Bell W A study of cutaneous photosensitivity induced by amiodarone.Br J Dermatol. 1985; 113: 537-549Crossref PubMed Scopus (58) Google Scholar, 7Vos AK van Ramshorst AGS Grosfeld JCM Goossens JP A peculiar cutaneous pigmentation from Cordarone.Dermatologica. 1972; 145: 297-303Crossref PubMed Scopus (33) Google Scholar by electron microscopy, it appears to be membrane bound;8Delage C Lagacé R Huard J Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study.Can Med Assoc J. 1975; 112: 1205-1208PubMed Google Scholar and by electron probe analysis, high concentrations of iodine are found.9Trimble JW Mendelson DS Fetter BP Ingram P Gallagher JJ Shelburne JD Cutaneous pigmentation secondary to amiodarone therapy.Arch Dermatol. 1983; 119: 914-918Crossref PubMed Scopus (45) Google Scholar The presence of iodine suggests that the skin deposits are amiodarone itself or a metabolite. Photosensitivity reactions from amiodarone occur frequently (in more than 50% of patients) and may be a prerequisite for the subsequent development of blue-gray discoloration. Photosensitivity has been deemed a phototoxic reaction, and phototesting of patients suggested that ultraviolet A light in 350- to 380-nm wavelengths was primarily responsible. Ultraviolet B light elicits the effect in vitro but is probably less important clinically because of absorption of ultraviolet B light in the epidermis.6Ferguson J Addo HA Jones S Johnson BE Frain-Bell W A study of cutaneous photosensitivity induced by amiodarone.Br J Dermatol. 1985; 113: 537-549Crossref PubMed Scopus (58) Google Scholar As little as 200 mg/day of amiodarone has been demonstrated to decrease the ultraviolet A light minimal erythema dose by 50%. After cessation of therapy, phototesting revealed substantially decreased photosensitivity at 1 year, but residual improvement from year 1 to year 2 was also seen. Symptoms of photosensitivity generally began to diminish 4 months after use of the drug had been discontinued.1McKenna WJ Rowland E Krikler DM Amiodarone: the experience of the past decade.Br Med J. 1983; 287: 1654-1656Crossref PubMed Scopus (30) Google Scholar, 6Ferguson J Addo HA Jones S Johnson BE Frain-Bell W A study of cutaneous photosensitivity induced by amiodarone.Br J Dermatol. 1985; 113: 537-549Crossref PubMed Scopus (58) Google Scholar, 10Chalmers RJG Muston HL Srinivas V Bennett DH High incidence of amiodarone-induced photosensitivity in North-west England.Br J Med. 1982; 285: 341Crossref PubMed Scopus (43) Google Scholar, 11Zachary CB Slater DN Holt DW Storey GCA MacDonald DM The pathogenesis of amiodarone-induced pigmentation and photosensitivity.Br J Dermatol. 1984; 110: 451-456Crossref PubMed Scopus (82) Google Scholar, 12Rappersberger K Hönigsmann H Ortel B Tanew A Konrad K Wolff K Photosensitivity and hyperpigmentation in amiodarone-treated patients: incidence, time course, and recovery.J Invest Dermatol. 1989; 93: 201-209Abstract Full Text PDF PubMed Google Scholar Several reports that described the outcome of patients with amiodarone-induced blue-gray cutaneous discoloration after cessation of therapy or reduction in dose are summarized in Table 1. All these case reports are anecdotal and did not control for exposure to sunlight, but they emphasize that the blue-gray color is limited to sunlight-exposed skin. Most patients in whom discoloration develops have received the drug for prolonged periods, usually in dosages of 400 to 800 mg/day.7Vos AK van Ramshorst AGS Grosfeld JCM Goossens JP A peculiar cutaneous pigmentation from Cordarone.Dermatologica. 1972; 145: 297-303Crossref PubMed Scopus (33) Google Scholar, 8Delage C Lagacé R Huard J Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study.Can Med Assoc J. 1975; 112: 1205-1208PubMed Google Scholar, 11Zachary CB Slater DN Holt DW Storey GCA MacDonald DM The pathogenesis of amiodarone-induced pigmentation and photosensitivity.Br J Dermatol. 1984; 110: 451-456Crossref PubMed Scopus (82) Google Scholar, 12Rappersberger K Hönigsmann H Ortel B Tanew A Konrad K Wolff K Photosensitivity and hyperpigmentation in amiodarone-treated patients: incidence, time course, and recovery.J Invest Dermatol. 1989; 93: 201-209Abstract Full Text PDF PubMed Google Scholar, 13Geerts ML Amiodarone pigmentation: an electron microscopic study.Arch Belg Dermatol Syphiligr. 1971; 27: 339-351PubMed Google Scholar, 14Harris L McKenna WJ Rowland E Holt DW Storey GCA Krikler DM Side effects of long-term amiodarone therapy.Circulation. 1983; 67: 45-51Crossref PubMed Scopus (298) Google Scholar, 15Weiss SR Lim HW Curtis G Slate-gray pigmentation of sun-exposed skin induced by amiodarone (letter to the editor).J Am Acad Dermatol. 1984; 11: 898-900Abstract Full Text PDF PubMed Scopus (11) Google Scholar, 16Beukema WP Graboys TB Spontaneous disappearance of blue-gray facial pigmentation during amiodarone therapy (out of the blue).Am J Cardiol. 1988; 62: 1146-1147Abstract Full Text PDF PubMed Scopus (10) Google Scholar Thus, some investigators have proposed a dose-duration requirement for the development of blue-gray pigmentation.8Delage C Lagacé R Huard J Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study.Can Med Assoc J. 1975; 112: 1205-1208PubMed Google Scholar Two case reports suggest that additional factors may be involved. One patient had worsening of discoloration for 6 months after cessation of use of amiodarone.15Weiss SR Lim HW Curtis G Slate-gray pigmentation of sun-exposed skin induced by amiodarone (letter to the editor).J Am Acad Dermatol. 1984; 11: 898-900Abstract Full Text PDF PubMed Scopus (11) Google Scholar In a case report by Beukema and Graboys,16Beukema WP Graboys TB Spontaneous disappearance of blue-gray facial pigmentation during amiodarone therapy (out of the blue).Am J Cardiol. 1988; 62: 1146-1147Abstract Full Text PDF PubMed Scopus (10) Google Scholar blue-gray discoloration gradually disappeared during a period of 51 months despite continued oral use of amiodarone at a reduced dosage of 200 mg/day. These data suggest that a threshold tissue level exists, above which abnormal color may develop in skin exposed to sunlight.Table 1Summary of Reported Observations in Patients With Amiodarone-Induced Hyperpigmentation After Cessation of Therapy or Reduction in DoseDoseDuration (mo)ReferenceNo. of patientsDaily (mg)Total (g)On therapyOff therapyObservationVos et al7Vos AK van Ramshorst AGS Grosfeld JCM Goossens JP A peculiar cutaneous pigmentation from Cordarone.Dermatologica. 1972; 145: 297-303Crossref PubMed Scopus (33) Google Scholar1600348197No clinical improvementDelage et al8Delage C Lagacé R Huard J Pseudocyanotic pigmentation of the skin induced by amiodarone: a light and electron microscopic study.Can Med Assoc J. 1975; 112: 1205-1208PubMed Google Scholar1200–40090–1801517No disappearance of pigmentationZachary et al11Zachary CB Slater DN Holt DW Storey GCA MacDonald DM The pathogenesis of amiodarone-induced pigmentation and photosensitivity.Br J Dermatol. 1984; 110: 451-456Crossref PubMed Scopus (82) Google Scholar1800596246Persistent pigmentationRappersberger et al12Rappersberger K Hönigsmann H Ortel B Tanew A Konrad K Wolff K Photosensitivity and hyperpigmentation in amiodarone-treated patients: incidence, time course, and recovery.J Invest Dermatol. 1989; 93: 201-209Abstract Full Text PDF PubMed Google Scholar12002404033Gradual fading, restoration of skin colorGeerts13Geerts ML Amiodarone pigmentation: an electron microscopic study.Arch Belg Dermatol Syphiligr. 1971; 27: 339-351PubMed Google Scholar3400–600216–324186–12Pigmentation did not fadeHarris et al14Harris L McKenna WJ Rowland E Holt DW Storey GCA Krikler DM Side effects of long-term amiodarone therapy.Circulation. 1983; 67: 45-51Crossref PubMed Scopus (298) Google Scholar2600438246–12Pigmentation still present6001,09560Weiss et al15Weiss SR Lim HW Curtis G Slate-gray pigmentation of sun-exposed skin induced by amiodarone (letter to the editor).J Am Acad Dermatol. 1984; 11: 898-900Abstract Full Text PDF PubMed Scopus (11) Google Scholar1800 (5 mo)216136Blue-gray discoloration persisted and increased400 (8 mo)Beukema & Graboys16Beukema WP Graboys TB Spontaneous disappearance of blue-gray facial pigmentation during amiodarone therapy (out of the blue).Am J Cardiol. 1988; 62: 1146-1147Abstract Full Text PDF PubMed Scopus (10) Google Scholar1600 (4 mo)2181651*Lower dosage (200 mg/day).Faded after 48 mo at lower dosage400 (12 mo)* Lower dosage (200 mg/day). Open table in a new tab The tissue concentration of amiodarone should be related not only to the daily dose but also to the rate of elimination. The half-life of amiodarone averages 52 days but may exceed 100 days. It is prolonged in patients with hepatic insufficiency and is probably longer for the active first metabolite, desethylamiodarone, than the parent compound. The slow rate of elimination and the uptake by fat-associated tissues of up to 500 times the serum concentration (and more than 10 times the myocardial concentration) may explain the delayed disappearance of cutaneous photosensitivity and the late resolution of blue-gray discoloration.17Haffajee CI Clinical pharmacokinetics of amiodarone.Clin Cardiol. 1987; 10: I6-I9PubMed Google Scholar, 18Mason JW Amiodarone.N Engl J Med. 1987; 316: 455-466Crossref PubMed Scopus (465) Google Scholar The more rapid fading of the hyperpigmentation in our patient (18 months in contrast with the usual 3 to 5 years) may reflect diligent avoidance of sunlight plus some benefit from the bleaching cream, which may have decreased the basal layer melanin that contributed to the discoloration. Because ultraviolet A wavelengths are chiefly at fault, conventional sunscreens do not provide adequate protection. Clinical studies suggest that zinc oxide (an opaque barrier) or ultraviolet A sunscreens effectively reduce the phototoxic reactions induced by amiodarone.1McKenna WJ Rowland E Krikler DM Amiodarone: the experience of the past decade.Br Med J. 1983; 287: 1654-1656Crossref PubMed Scopus (30) Google Scholar, 4Walter JF Bradner H Curtis GP Amiodarone photosensitivity.Arch Dermatol. 1984; 120: 1591-1594Crossref PubMed Scopus (27) Google Scholar, 6Ferguson J Addo HA Jones S Johnson BE Frain-Bell W A study of cutaneous photosensitivity induced by amiodarone.Br J Dermatol. 1985; 113: 537-549Crossref PubMed Scopus (58) Google Scholar, 10Chalmers RJG Muston HL Srinivas V Bennett DH High incidence of amiodarone-induced photosensitivity in North-west England.Br J Med. 1982; 285: 341Crossref PubMed Scopus (43) Google Scholar, 11Zachary CB Slater DN Holt DW Storey GCA MacDonald DM The pathogenesis of amiodarone-induced pigmentation and photosensitivity.Br J Dermatol. 1984; 110: 451-456Crossref PubMed Scopus (82) Google Scholar, 12Rappersberger K Hönigsmann H Ortel B Tanew A Konrad K Wolff K Photosensitivity and hyperpigmentation in amiodarone-treated patients: incidence, time course, and recovery.J Invest Dermatol. 1989; 93: 201-209Abstract Full Text PDF PubMed Google Scholar, 19Ferguson J de Vane PJ Wirth M Prevention of amiodarone-induced photosensitivity (letter to the editor).Lancet. 1984; 2: 414Abstract PubMed Scopus (13) Google Scholar Additional recommended protective measures include a broad-brimmed hat, avoidance of short sleeves and shorts, and avoidance of thin cotton clothing. These methods should be continued for at least 6 months after cessation of use of the drug to allow the tissue level to decline sufficiently to minimize the possibility of phototoxicity. In addition, because at least part of the discoloration can be attributed to increased melanin, the use of a bleaching agent should be considered. In general, the data from previously published reports of amiodarone-induced hyperpigmentation and the course of our current patient support the reversibility of the blue-gray cutaneous discoloration in cases in which follow-up is extended. The question of how long sunscreen and barrier precautions should be recommended after cessation of use of the drug remains unanswered.