Abstract: Minocycline-induced hyperpigmentation of tissues has been documented previously, but extensive cardiovascular involvement is rarely described in literature. We report a case of marked cardiovascular hyperpigmentation resulting from approximately 4 years of minocycline exposure. We will highlight how intraoperative differentiation of minocycline-induced hyperpigmentation from more sinister causes of discoloration led to the appropriate surgical management. Minocycline-induced hyperpigmentation of tissues has been documented previously, but extensive cardiovascular involvement is rarely described in literature. We report a case of marked cardiovascular hyperpigmentation resulting from approximately 4 years of minocycline exposure. We will highlight how intraoperative differentiation of minocycline-induced hyperpigmentation from more sinister causes of discoloration led to the appropriate surgical management. Minocycline-induced hyperpigmentation (MIH) of tissues has been previously documented with minocycline use, with hyperpigmentation sometimes affecting the cardiovascular system. Cutaneous and mucosal MIH may be observed upon history and physical examination, but MIH attributable to long-term use of minocycline (>30 years) has also been discovered intraoperatively and at autopsy in an array of tissues, including the cardiovascular system [1Tsunekawa T. Jones K. Doty J. Black pigmented aortic valve and sinus of Valsalva caused by life-long minocycline therapy.Interact Cardiovasc Thorac Surg. 2014; 19: 339-340Crossref PubMed Scopus (11) Google Scholar]. The patient in the following case demonstrates marked cardiovascular MIH following approximately 4 years of minocycline treatment. We describe the intraoperative dilemma and highlight how differentiation of MIH from more sinister possible etiologies helped to facilitate appropriate surgical management and prevent unwarranted patient morbidity and mortality. A 56-year-old man with existing coronary artery atherosclerotic disease developed significant endocarditis necessitating mitral and aortic valve repair. The initial intraoperative course proceeded uneventfully. After median sternotomy and pericardial reflection, a bluish discoloration of the aorta and coronary arteries was noted, raising concern for an occult aortic dissection (Fig 1). Intraoperative transesophageal echocardiography could not rule out the possibility of an abnormal wall arising from the distal ascending aorta extending into the arch, and the blue color appeared consistent with intramural thrombus. The presence of dissection would have necessitated aortic arch replacement with coronary artery reimplantation. Axillary cannulation was then performed, and the patient was placed on cardiopulmonary bypass. The aorta, aortic valve, and coronary arteries were all discolored. The utility of abandoning the surgery, performing intraoperative fluoroscopy, or transporting the patient for CT or magnetic resonance imaging were considered, but eventually an intraoperative pathology consultation was requested. Frozen section microscopy revealed the presence of blue-black granular pigment in the intimal layer of the aorta without architectural damage (Fig 2). The vessel wall was negative for intramural thrombus or dissection, but it displayed focal mineralization without calcification and intralaminar deposition of pigment within the aortic valve, aortic wall, and coronary artery tissue specimens. Benign pigmentation was the working diagnosis, with tetracycline-associated pigmentation and ochronosis as possible differentials. Blue-tinged sclera, nail beds, superficial lower extremity vasculature, dentition, and gums were noted on further physical examination. Of the patient’s known medications (omeprazole [Zegerid], verapamil, hydrochlorothiazide, valsartan [Diovan], and simvastatin [Zocor), no causative agent for these phenomena was identified. However, during a specific inquiry, a 4-year history of minocycline (100 mg TID) therapy was elicited from the family physician.Fig 2Microscopy showing laminar deposition of granular pigment in the aortic valve (hematoxylin and eosin, original magnification × 10).View Large Image Figure ViewerDownload Hi-res image Download (PPT) Differential diagnoses for blue-black tissue pigmentation includes heavy metal deposition, alkaptonuria (ochronosis), and a classic collection of pharmaceutical agents. Minocycline is a tetracycline derivative that inhibits bacterial protein synthesis and is known to cause discoloration with chronic usage. It is used as a broad spectrum bacteriostatic agent and anti-inflammatory for the treatment of acne and rheumatoid arthritis. Other documented side effects of minocycline use include black thyroid syndrome, black bone disease, black galactorrhea, acute renal failure, diarrhea, hepatotoxicity, myocarditis, drug reaction with eosinophilia, drug-induced hypersensitivity syndrome, drug-induced vasculitis, and systemic lupus erythematosus, but hyperpigmentation is commonly reported and considered a benign cosmetic nuisance [2Joshi H. Chhikara V. Arya K. Pathak R. Some undesirable effects reported in past five years related to minocycline therapy: a review.Ann Biol Res. 2010; 1: 64-71Google Scholar]. Theories explaining the mechanism of minocycline pigment deposition include direct drug enhancement of melanocytes, insoluble drug-iron complex formation, and production of pigment metabolites resulting from drug oxidation [3Zuckerman M. Boyle K. Rosenbaum C. Minocycline Toxicity: case files of the University of Massachusetts medical toxicology fellowship.J Med Toxicol. 2012; 8: 304-309Crossref Scopus (4) Google Scholar]. Generally, pigmentation appears to be linked to duration of use among high-dose users and subsequently regresses with drug termination. Although MIH of the oral mucosa and palate, nail beds, sclera, and face have been seen with as little as two weeks of therapy, deposition in the thyroid gland, teeth, bone, heart valves has classically been associated with a higher cumulative dosage (>100 g) or longer exposure [1Tsunekawa T. Jones K. Doty J. Black pigmented aortic valve and sinus of Valsalva caused by life-long minocycline therapy.Interact Cardiovasc Thorac Surg. 2014; 19: 339-340Crossref PubMed Scopus (11) Google Scholar, 3Zuckerman M. Boyle K. Rosenbaum C. Minocycline Toxicity: case files of the University of Massachusetts medical toxicology fellowship.J Med Toxicol. 2012; 8: 304-309Crossref Scopus (4) Google Scholar, 4Filitis D. Graber E. Minocycline-induced hyperpigmentation involving the oral mucosa after short-term minocycline use.Cutis. 2013; 92: 46-48PubMed Google Scholar]. Aside from dose and duration, MIH can be variably inhibited by ascorbic acid, exacerbated by sun exposure, and ameliorated by laser treatment [2Joshi H. Chhikara V. Arya K. Pathak R. Some undesirable effects reported in past five years related to minocycline therapy: a review.Ann Biol Res. 2010; 1: 64-71Google Scholar, 3Zuckerman M. Boyle K. Rosenbaum C. Minocycline Toxicity: case files of the University of Massachusetts medical toxicology fellowship.J Med Toxicol. 2012; 8: 304-309Crossref Scopus (4) Google Scholar]. This case demonstrates dramatic minocycline-induced pigmentation showing predominantly black pigment deposition in the aorta and aortic valve after 4 years of treatment. The phenomenon of MIH has been reported in skin, connective tissue, various internal organs, coronary arteries, aortic valve, and the sinus of Valsalva [1Tsunekawa T. Jones K. Doty J. Black pigmented aortic valve and sinus of Valsalva caused by life-long minocycline therapy.Interact Cardiovasc Thorac Surg. 2014; 19: 339-340Crossref PubMed Scopus (11) Google Scholar, 4Filitis D. Graber E. Minocycline-induced hyperpigmentation involving the oral mucosa after short-term minocycline use.Cutis. 2013; 92: 46-48PubMed Google Scholar], but a specific presentation that could have resulted in significant intraoperative patient mortality and morbidity has not been previously described, to our knowledge. We believe this to be the first documented case of minocycline-induced vascular pigmentation that was sufficiently advanced to appear consistent with aortic and coronary artery dissection. Awareness of the potential variation in extent of minocycline pigmentation broadens the differential diagnosis when faced with intraoperative vascular discoloration inconsistent with perioperative workup. In addition, efficient interdepartmental collaboration enables appropriate diagnosis and responsible surgical management, preventing unwarranted patient morbidity or mortality.
Publication Year: 2017
Publication Date: 2017-02-01
Language: en
Type: article
Indexed In: ['crossref', 'pubmed']
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Cited By Count: 6
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