Aortic valve ochronosis: a rare manifestation of alkaptonuria

Abstract

Alkaptonuric ochronosis is a heritable disorder of tyrosine metabolism, with various systemic abnormalities related to pigment deposition and degeneration of collagen and other tissues, including the heart and aorta.

A 65-year-old woman with alkaptonuric ochronosis and a history of four joint replacements required aortic valve replacement for severe aortic stenosis. Operative findings included ochronosis of a partly calcified aortic valve and the aortic intima. The aortic valve was removed at surgery and histologically investigated. Light microscopic examination of the aortic valve revealed intracellular and extracellular deposits of ochronotic pigment and a chronic inflammatory infiltrate.

Beside the case representation, the disease history, aetiology, pathogenesis, clinical presentation and treatment of aortic valve ochronosis are reviewed.

Background

Alkaptonuria, a rare autosomal recessive gentic disorder of tyrosine metabolism, is associated with homogentisic acid oxydase enzyme deficiency and characterised by accumulation of homogentisic acid in extracellular tissues. The responsible gene is on chromosome 3q, with various mutations in the gene.¹

The diagnosis is usually made from the triad of degerative arthritis, ochronotic connective tissue pigmentation and urine that turns dark brown or black on alkalisation.

The most common clinical features are pigmentation of the skin, sclerae and ear cartilage; and ochronotic arthropathy affecting mainly the vertebral discs and large joints. Less common manifestations include renal, urethral and prostate calculi and cardiovascular abnormalities, especially valvular disease.

Alkaptonuria affects between 1 in 250 000 to 1 in 1 000 000 people,² although in some areas such as Slovakia and the Dominican Republic,³ the incidence is much higher (eg, up to 1 in 19 000 in Slovakia).⁴ The disease was even detected in an Egyptian mummy⁵ and from mediaeval times, there are descriptions of the disease which were, however, misinterpreted at that time.

Scibonius first described the urinary manifestations of the disease in 1584,⁶ but Virchow was the first who used the term alkaptonuria in 1866 to describe the urine’s affinity for the alkali solution.⁷

By 1908, Garrod had proposed that, alkaptonuria was an inborn error of metabolism⁸ and by 1909, Neubauer had mapped the complete tyrosine-degradation pathway.⁹

Case presentation

This article reports a case of aortic stenosis associated with ochronosis in a 65-year-old woman with a history of dark urine since childhood. She had no evidence of rheumatic fever or endocarditis, but a history of bilateral total hip and knee replacements was noted due to progressive degenerative arthritis affecting the hips, knees and spine beginning in her late 40s. No one in the patient’s family had reported symptoms or signs compatible with the syndrome of alkaptonuria.

Concerning the aortic stenosis, the patient remained relatively asymptomatic until several weeks before assessment, when she experienced a new onset increasing exertional dyspnoea. Echocardiographic findings revealed a severe aortic stenosis with 65 mm Hg and 45 mm Hg peak and mean transvalvular gradients, respectively. The calculated aortic valve area was 0.45 cm². The left ventricular function was normal. Cardiac catheterisation confirmed the diagnosis and revealed normal coronary arteries. The results of routine laboratory tests were inconspicuous.

The patient underwent open heart surgery in September 2007. Cardiopulmonary bypass was instituted by ascending aortic and monocaval cannulation and cold crystalloid cardioplegic solution was administered ante- and retrogradely. Oblique aortotomy revealed a black pigmentation of the intima of the aortic wall and a tricuspid aortic valve with three normal-sized cusps with thickened and nodular calcified dark black leaflets. No commisural fusion was seen. There was no evidence of infective endocarditis. The aortic valve leaflets were resected, the annulus was decalcified and a 21 mm Medtronic-Mosaic Ultra Porcine valve was implanted. Postoperatively, atrial fibrillation of the patient was successfully treated by amiodarone therapy. The patient was discharged from hospital 13 days after surgery without any complications.

Investigations

Microscopically, the collagen of the aortic valve showed brown pigment deposition within the ossified and calcified areas and focally even in the non-calcified valvular tissue. The pigment deposition was both found intra and extracellular and was variable in character with some areas coarsely granular, similar to haemosiderin and other areas finely granular. Within the calcified areas, a considerable vascularisation and a chronic inflammatory infiltrate, consisting of pigment-laden macrophages, plasma cells and lymphocytes could also be observed (figure 1A). Additionally to calcified and fibrotic areas of the aortic valve, focally a mucoid degeneration of the connective tissue was noticed (figure 1B,C).

Figure 1.

(A) Massive calcification and ossification of the aortic valve surrounded by chronic inflammatory infiltrate. The macrophags showed an intracellular pigmentation. (H&E staining, orginal magnification ×10). (B, C) Within the calcified areas and the fibrotic tissue a coarsely granulated brown pigment could be noticed. Beside the pigmented, areas deposits of acid mucopolysaccharids could be observed (H&E staining, original magnification ×40).

Outcome and follow-up

Currently, the patient is free from any symptoms related to the cardiovascular system for 3 years following aortic valve replacement.

Discussion

The most common serious effect of alkaptonuric ochronosis is the development of ochronotic arthropathy. But patients become more mobile after aggressive joint therapy including total joint replacement, and with increasing age clinical cardiovascular symptoms may manifest.

Although several reports have been published in recent years,^{10 11} it is difficult to assess the incidence of cardiac ochronosis accurately because of its rarity. Ochronosis has been associated with pigmentation of various structures in the cardiovascular system including the leaflets, annulus and roots of valves, endocardium, subendocardium and pericardium, all three layers of arterial walls and in the atherosclerotic plaques of the aorta and coronary arteries. The pigment is deposited in an extracellular and intracellular location, with smooth-muscle cells, makrophags, fibroblasts being affected.^{12 13} It has previously been suggested, that the deposition of ochronotic pigment in vascular endothelium could lead to the initial injury responsible for the genesis of atheroma and coronary artery disease, because ochronotic pigmentation has been described in macrophages and smooth-muscle cells of the aortic media.¹⁴ Old myocardial scars including infarcts and fibrotic papillary muscles may also become pigmented.¹³

Some case series have showed no increase in frequency of calcification and stenosis of aortic valves or coronary artery disease^{15 16} but numerous other observations suggest, that ochronosis may be associated with coronary disease. In a series of 58 ochronotic patients, three (5.2%) had aortic valve replacement, and 50% had CT evidence of coronary artery calcification by 59 years of age.¹⁷

It is generally accepted, that aortic valvular stenosis is the most frequent cardiac manifestation of the disease; however, aortic and mitral regurgitation have also been described.^{18 19} The pigment is usually most marked at the valve cusp or leaflet base extending into the valve annulus.¹⁴ The aortic valve has the highest incidence of calcifications and stenosis, followed by the mitral and pulmonary valves, but involvement of multiple valves may be observed.

The valve disease usually occurs in patients of at least middle age (mean age 54 years)¹⁷ because the pigment must accumulate. The youngest patient reported was 26 years old.¹⁴ The distribution of this disease is equal in males and females. Males tend to have an earlier onset of arthritic symptoms with a greater degree of severity than females, although the reason for this difference is ambiguous.²⁰

The pathogenesis of cardiovascular ochronosis is still unclear, but is probably related to the extensive extracellular deposits of ochronotic pigment in the cardiac tissue.

Similar to this case, Gaines and Pai¹² identified extensive extracellular deposits of ochronotic pigment in the aortic valve of a 64-year-old male patient and suggested that, the anatomical derangement of the valves is caused by the degeneration of pigment-laden fibrocytes, which leads to fibrosis of the valve substance and progressive calcification. Although unproven, the deposition of polymer is assumed to also cause an inflammatory response that results in calcium deposition in affected tissues.

Even though there is no effective treatment for alkaptonuria, the prognosis is relatively good.²¹ Therapy is directed at dealing with the complications of the disease.

Alkaptonuria-associated arthritis is treated symptomatically with the use of nonsteroidal anti-inflammatory drugs or total joint replacement.

High doses of ascorbic acid, approximately 1000 mg daily, has been proposed as a method to avoid deposition of homogentisic acid in body tissues and may therefore prevent or delay subsequent symptoms.²²

Nitisinone, a potent inhibitor of 4-hydroxyphenylpyruvate dioxygenase, dramatically reduces production and urinary excretion of homogentisic acid²³; however, the long-term efficacy and side effects of such therapy are unknown. But identifying the gene for alkaptonuria offers the potential for a promising new therapeutic approach.

In conclusion, cardiac ochronosis is a very rare disease, but cardiac surgeons and pathologists should be aware of this condition since they might be confronted with the typical signs during elective cardiac surgery and histological examination of excised specimens.

Learning points.

• ▶Alkaptonuria, a rare autosomal genetic disorder of tyrosine metabolism, is characterised by accumulation of homogentisic acid in extracellular tissues, and commonly affects the large joints, the vertebral discs, the skin, sclerae and ear cartilage.
• ▶Ochronosis has also been associated with cardiovascular abnormalities concerning the valves, the endocardium, subendocardium and pericardium, the aorta and coronary arteries with aortic valve stenosis being by far the most common cardiovascular manifestation of the disease.
• ▶An effective treatment for alkaptonuria does not exist, and therapy is directed at dealing with the complications of the disease.