Case report. A 73-year-old male presented to his cardiologist with complaints of dyspnea on exertion over the past two years. The dyspnea had been progressively worsening over the previous three months, to the point where the patient had to stop and rest after walking up a half flight of stairs. Over the past month, the dyspnea had become associated with central chest pressure radiating down the left arm. Past medical history included osteoarthritis involving the knees and hips, hypertension, hyperlipidemia, GERD, and rheumatic fever as a child. Review of symptoms revealed diffuse debilitating joint pain in addition to his presenting complaints. Medications included aspirin 325 mg q.d., captopril 25 mg t.i.d., diclofenac, and isosorbide dinitrate 40 mg t.i.d. Physical examination revealed a regular pulse of 76/minute, with a blood pressure of 128/70, a delayed and diminished carotid upstroke, and a loud 4/6 late-peaking basal systolic murmur radiating to the neck, as well as a 2/6 early diastolic murmur at the base; lungs were clear and there was no lower extremity edema. Routine laboratory values were normal. The patient also had a bluish pigmentation of his ears (Figure 1A), as well as dark pigmentation of the sclerae (Figure 1B) and lips (Figure 1C). An echocardiogram demonstrated normal left ventricular systolic function, mitral annular calcification with moderate mitral regurgitation, aortic stenosis with a calculated valve area of 0.9 cm2, and moderate-to-severe aortic insufficiency. The patient was scheduled for cardiac catheterization to further delineate the severity of his aortic stenosis, as well as to assess the presence and extent of coronary artery disease and pulmonary hypertension. At catheterization, the patient was found to have severe left main and three-vessel coronary disease. His calculated aortic valve area was 0.6cm2, and his pulmonary pressures were normal. Left ventricular ejection fraction was calculated at 50%. The patient was subsequently admitted for coronary artery bypass graft surgery and aortic valve replacement (AVR) the following day. Following sternotomy in the operating room, it was noted that the sternum and ribs were darkly pigmented with a blue-black deposit. Upon opening of the pericardium, it was noted that the ascending aorta possessed a dark hue, somewhat suggestive of an aortic dissection with a resultant intramural hematoma (Figure 2). Transesophageal echocardiogram performed intraoperatively failed to show evidence of aortic dissection or intramural hematoma. Following aortotomy, it was noted that the intimal surface of the aorta was also darkly pigmented. There was heavy calcification of the aortic valve extending into the aortic root and involving the coronary ostia. The coronary arteries themselves were also heavily calcified and were noted to have blackened intimal surfaces, which were more pronounced in areas of atherosclerotic plaquing. Biopsies were taken of the sternal bone and of a section of the aortic wall. Pathologic testing revealed a positive staining with melanin, as well as a focal area of pigmentation with associated aortic dissection and degeneration within the aortic media (Figures 3 A and B), as well as pigment deposition in the sternal bone (Figure 3 C), consistent with the diagnosis of ochronosis secondary to alkaptonuria. Discussion. Alkaptonuria is a rare genetic disorder occurring in one of 250,000 to 1 million live births. It is an autosomal recessive inborn error of metabolism involving an absence of the enzyme homogentisic acid oxidase, which is responsible for the degradation of homogentisic acid, formed by the breakdown of the amino acids phenylalanine and tyrosine. This deficiency leads to excretion of homogentisic acid in the urine which causes the urine to turn dark when it is allowed to stand, due to oxidation to a melanin-like product. Homogentisic acid also gradually accumulates in connective tissues, causing a bluish-black pigmentation which Virchow coined “ochronosis” in 1866.1 This pigmentation usually begins in the third to fourth decade of life, and most commonly involves the skin, ears, and sclerae. Ochronotic deposits in the joints and spine cause an arthropathy that is the most common clinical manifestation of the disease. The hips, shoulders, and knees are often involved, causing lower back pain and stiffness. This can be associated with intervertebral disc ossification and “bony bridging,” leading to a “bamboo spine” appearance on X-ray, and often leading to the incorrect diagnosis of Ankylosing Spondylitis.2,3 Although less common than ochronotic arthropathy, cardiovascular ochronosis can occur due to pigment deposition in valvular and endovascular tissue. These deposits have been associated with valvular disease, most commonly aortic stenosis. In a review of the English language literature between 1940 and 1990 by Kenny et al., 13 patients with cardiovascular ochronosis were identified.4 Twelve patients had aortic valve involvement, eight had mitral valve involvement, and three had pulmonic valve involvement. All patients in this series had extensive atherosclerosis and pigmentation of the aorta, and seven of eight patients in whom the coronary anatomy was described at autopsy had coronary artery disease with associated pigmentation. Vavuranakis et al. describe a patient presenting with angina and congestive heart failure found to have severe aortic stenosis and coronary artery disease with dense extracellular homogentisic acid deposits on the aortic cusps at pathologic examination following AVR.5 In addition, they postulated that his coronary artery disease, as well as his significant peripheral vascular disease, was in part due to intracellular pigment deposition in the arterial intima, although direct tissue sampling of the intima was not obtained. Helou et al. describe a case similar to ours involving a male patient referred for coronary artery bypass grafting and aortic valve replacement, and was found during surgery to have ochronosis on direct visualization of the heart and great vessels.6 Microscopic examination confirmed the presence of granular pigment both intra- and extracellular in location. A recently published study analyzed the natural history of alkaptonuria in 58 patients. Cardiac valve involvement was detected in 50% of patients by age 54, and coronary artery calcification in 50% of patients by age 59. Interestingly, serum cholesterol levels did not correlate with calcification of the coronary arteries.3 The precise mechanism for connective tissue changes related to pigment deposition is unclear. One theory claims that the ochronotic pigment itself is a chemical irritant, producing inflammation and accelerated degenerative changes in connective tissue. Another theory suggests that the pigment acts as an enzyme inhibitor, thereby altering normal cartilage metabolism.2 Although several treatment approaches have been attempted, there is no effective treatment for alkaptonuria. Trials with high-dose vitamin C, as well as dietary restrictions of protein intake (or specific restrictions on tyrosine and phenylalanine intake), have failed to reduce urinary levels of homogentisic acid. Phornphutal et al. believe that efforts to pharmacologically reduce the production of homogentisic acid should be investigated. They suggest that nitisinone, an herbicide that reversibly inhibits 4-hydroxyphenylpyruvate dioxygenase (the enzyme that catalyzes the final step in homogentisic acid production), may be of some benefit.3 However, this approach causes plasma tyrosine levels to increase dramatically, resulting in corneal irritation, as well as possible neurologic and dermatologic side effects. In conclusion, we present a case of known alkaptonuria and cardiovascular ochronosis diagnosed during open heart surgery. The fact that the initial gross appearance of the aorta upon direct visualization following sternotomy prompted concern regarding the possibility of aortic dissection with intramural hematoma demonstrates that this rare condition should also be considered under such circumstances. Furthermore, this case reminds us of the need to remember this rare but important disease as part of the differential diagnosis when evaluating patients with aortic stenosis who have a history of arthropathy, as well as the value of incorporating dermatologic and musculoskeletal evaluations into a thorough physical examination in order to identify manifestations of important cardiovascular disease processes in other organ systems.
1. Virchow R. Ein fall von allgemeiner ochronose der knorpel und knorpelahnlichen theile. Virchows Arch Path Anat Physiol 1866;37:212‚Äì219. 2. Resnick D. Diagnosis of Bone and Joint Disorders (4th ed). Philadelphia: W.B. Saunders Co., 2002, 1678‚Äì1694. 3. Phornphutkul C, Introne WJ, Perry MB, et al. Natural history of alkaptonuria. N Engl J Med 2002;347:2111‚Äì2221. 4. Kenny D, Ptacin MJ, Bamrah VS, Almagro U. Cardiovascular ochronsis: A case report and review of the medical literature. Cardiology 1990;77:477‚Äì483. 5. Vavuranakis M, Triantafillidi H, Stefanadis C, Toutouzas P. Aortic stenosis and coronary artery disease caused by alkaptonuria, a rare genetic metabolic syndrome. Cardiology 1998;90:302‚Äì304. 6. Helou J, Masters RG, Keon WJ, Veinot JP. Ochronosis: An unusual finding at aortic valve replacement. Can J Cardiol 1999;15:1013‚Äì1015.