Case Report Cardiology 1998;90:302–304 Manolis Vavuranakis Helen Triantafillidi Christodoulos Stefanadis Pavlos Toutouzas Department of Cardiology, Hippokration Hospital, Athens, Greece Received: September 22, 1998 Accepted: October 9, 1998 Aortic Stenosis and Coronary Artery Disease Caused by Alkaptonuria, a Rare Genetic Metabolic Syndrome OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO Key Words Alkaptonuria Ochronosis Homogentisic acid Aortic stenosis Abstract Alkaptonuria is a rare metabolic disease in which homogentisic acid deposits occur in various body tissues. We present a case of alkaptonuria which resulted in aortic stenosis and coronary artery disease due to homogentisic acid deposition. OOOOOOOOOOOOOOOOOOOOOO Introduction Case Report ABC © 1999 S. Karger AG, Basel 0008–6312/98/0904–0302$17.50/0 Fax + 41 61 306 12 34 E-Mail firstname.lastname@example.org www.karger.com Accessible online at: http://BioMedNet.com/karger A 62-year-old white male was presented to our hospital with angina pectoris and dyspnea at rest (New York Heart Association class IV). He reported that his urine caused dark pigmentation on his underwear since infancy. On physical examination, the patient looked generally ill, had mild respiratory distress, and showed extended discoloration of the sclerae, the ears, and the skin of his hands. His arterial blood pressure was 95/70 mm Hg with a pulse rate of 116 beats/min. Radial, femoral, posterior tibial, and dorsalis pedis arteries were hardly palpable. Cardiovascular examination revealed regular heart rate and rhythm with decreased second heart sound and a detectable third heart sound at the apex of the heart. A systolic murmur two to three over six was present at the aortic valve area which radiated to the carotid arteries. Lung examination revealed basilar rales, while abdominal examination was normal. His urine after being exposed to room air in a urine cap or after being mixed with an alkali solution blackened. The electrocardiographic examination showed normal sinus rhythm and strain of the left ventricle. A chest X-ray showed several radiopaque deposits at the ascending and descending thoracic aorta and at the proximal segments of the coronary arteries which were visualized on plain chest X-ray films. X-ray of the spinal cord showed findings compatible with degenerative arthritis with narrowing of the intervertebral spaces and dense opacification of the intervertebral disks. The contour of the peripheral arteries could be detected on plain radiographic films of Manolis Vavuranakis, MD Department of Cardiology, University of Athens Hippokration Hospital, Haimanda 24–26, Marousi GR–15122 Athens (Greece) Tel. +30 1 8068466, Fax +30 1 7784590 Downloaded by: Univ.of Adelaide 220.127.116.11 - 10/26/2017 2:45:14 AM Alkaptonuria is a rare genetic metabolic syndrome which occurs approximately with an incidence of 1 in a million people [1, 2]. This syndrome is characterized by a deficiency of oxidase of homogentisic acid. This enzyme deficiency leads to accumulation of homogentisic acid, an intermediate product in the metabolism of tyrosine and phenylalaline, in connective tissues which is called ochronosis [3, 4]. The syndrome is inherited in an autosomal recessive pattern . Cardiovascular symptoms are rare, and the commonest symptoms are dark urine due to secretion of homogentisic acid and discoloration of the sclerae and ears at the age of 20–30 years [6, 7]. Virchow was the first who used the term alkaptonuria in 1866 to describe the urine’s affinity for the alkali solution. Alkaptonuria originated from the Greek words ‘·ÏÎ·´ ÏÈ’ (alkali) and ‘Î·´ Ùˆ’ (starve, need for) . the radiopaque deposits seen along the vessel wall. The transthoracic echocardiogram revealed a severely stenotic tricuspid aortic valve with a valve orifice of 0.4 cm2 and a peak gradient of 48 mm Hg. Echo-dense deposits on the aortic cusps were also observed. There was diffuse hypokinesia of the left ventricle. Doppler examination of the arteries of the lower limbs revealed no flow-limiting stenosis. Coronary angiography revealed severe coronary artery disease involving the proximal segments of the three main coronary arteries. Aortography documented severe limitation in the mobility of the aortic cusps. Aerochromatography of the urine showed large amounts of homogentisic acid. Skin biopsy specimens from the ear and the hands revealed the typical histological changes of alkaptonuria. The patient was diagnosed as having alkaptonuria which had affected the skin, the cartilage, and the cardiovascular system. His symptoms were mainly related to the cardiovascular involvement, and it was decided to proceed with aortic valve replacement and coronary bypass surgery. The patient had a successful surgery. His aortic valve was replaced with a prosthetic valve. Macroscopic and histologic features of his native aortic valve are shown in figures 1 and 2. Eight months after his cardiac surgery he does not manifest symptoms of angina or dyspnea in his daily activities. Discussion Our patient represents a typical case of alkaptonuria with all the clinical and histological features of the disease. Nevertheless, he was presented to our institution undiagnosed with symptoms related to the cardiovascular system, an unusual complication of the disease. Our patient had a history of dark urine which could be traced back to his infancy. He had progressive appearance of discolorations of the sclerae, ear, and hands and nails and Cardiovascular Involvement in Alkaptonuria Fig. 2. Histologically, homogentisic acid deposits are detected as black-brownish areas. HE. !80. had signs of degenerative arthritis of the spinal cord. Finally, he developed symptoms of angina and dyspnea due to coronary artery disease and severe aortic stenosis. We believe that aortic stenosis was secondary to homogentisic acid deposition on the aortic cusps. It is worth mentioning that no one in the patient’s family had reported symptoms or signs compatible with the syndrome of alkaptonuria. The patient’s only son had no homogentisic acid in his urine by aerochromatography, nevertheless he could still be heterozygotic individual, since no method for the detection of the heterozygotic state has been established yet [8–10]. In alkaptonuria, deposits of homogentisic acid in the cardiovascular system are usually located at the aortic valve where they are extracellular, the endocardium where they are intracellular, and in the vessel wall. As far as the vessel wall is concerned, the deposit can be located in the intima of the major arteries and within the atherosclerotic plaques. In the media they are usually surrounded by macrophages and smooth muscle cells. It should be noted that the media destruction does not lead to the formation of aneurysms. On the other hand, deposition of homogentisic acid in the vein wall has not been observed . We believe that the attenuated pulses in the peripheral arteries were due to the arterial wall involvement. We also believe that homogentisic acid deposits within the atherosclerotic plaques may have contributed to the development of coronary artery stenosis. We do not have histological specimens of the coronary lesion to confirm our hypothesis. Although there is no specific therapy for patients with alkaptonuria, their prognosis is considered relatively Cardiology 1998;90:302–304 303 Downloaded by: Univ.of Adelaide 18.104.22.168 - 10/26/2017 2:45:14 AM Fig. 1. Surgical specimen of the tricuspid aortic valve. The deformed valve with dense deposits of homogentisic acid producing a black surface area is seen. good. Administration of large amounts of vitamin C, approximately 1,000 mg daily, has been proposed as a method to avoid deposition of homogentisic acid in body tissues . On the other hand, the prognosis of alkaptonuria is poorer when the cardiovascular system is involved which is a rare complication of the disease. Degenerative arthritis is treated symptomatically with the use of nonsteroidal anti-inflammatory drugs. In conclusion, we present a case of alkaptonuria which was diagnosed at the age of 62 years due to cardiovascular involvement, an unusual complication of this rare syndrome. Physicians should be alert of this uncommon cause of aortic stenosis when evaluating such patients and seek other signs or symptoms which provide evidence for the disease. OOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOOO References 304 5 Bearn AG: Inborn errors of metabolism: Garrod’s legacy. Mol Med 1996;23;271–273. 6 Pyeritz RE: Genetics and cardiovascular disease; in Braunwald E (ed): Heart Disease: A Textbook of Cardiovascular Medicine, ed 5. Philadelphia, Saunders, 1996, p 1673. 7 Vlay CS, Hartman RA, Culliford TA: Alkaptonuria and aortic stenosis. Ann Intern Med 1986;104:446. 8 Presto Elgstoen KB, Jellum E: Capillary electrophoresis for diagnosis of metabolic disease. Electrophoresis 1997;18:1857–1860. Cardiology 1998;90:302–304 9 Deutsch JC, Santhosh Kumar CR: Quantitation of homogentisic acid in normal human plasma. 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