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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
Key Words
Homogentisic acid
Aortic stenosis
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.
Case Report
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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
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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 [5]. 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 ‘·Ïη´ ÏÈ’ (alkali)
and ‘η´ Ùˆ’ (starve, need for) [3].
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.
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
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 [3]. 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
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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 [11]. 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.
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Cardiology 1998;90:302–304
9 Deutsch JC, Santhosh Kumar CR: Quantitation of homogentisic acid in normal human
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R, Moore MM, Festen JJ, Sanmárti R, PeÒalva
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1, 2-dioxygenase gene in alkaptonuria patients.
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1 Kenny D, Ptacin MJ, Bamrah VS, Almagro U:
Cardiovascular ochronosis: A case report and
review of the medical literature. Cardiology
2 Carrod AE: The incidence of alkaptonuria: A
study in chemical individuality. Mol Med
3 La Du BN: Alkaptonuria; in Seriver CL, Beaudet AL, Sly WS, Valle D (eds): The Metabolic
and Molecular Bases of Inherited Disease, ed 7.
New York, McGraw-Hill, 1995, pp 1371–
4 Gaines JJ: The pathology of alkaptonuric ochronosis. Hum Pathol 1989;20:40–46.
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