Narrowing of the dark valve: aortic stenosis in alkaptonuria

Abstract

The commonest cardiac pathology in patients with alkaptonuria is aortic stenosis. Patients with alkaptonuria and aortic stenosis may remain asymptomatic until the 6th decade. Surgeons may have to deal with per-operative difficulties as alkaptonuria is a systemic disease. Proper preoperative planning is important. The mechanical valve prosthesis is advisable in a patient with alkaptonuria and aortic stenosis considering disease pathophysiology. We report a 70-year-old male diagnosed with alkaptonuria and aortic stenosis, who underwent aortic valve (mechanical valve prosthesis) and ascending aorta replacement.

Introduction

Alkaptonuria (ALK) is a rare autosomal recessive genetic disorder with a worldwide incidence of 1 per 250,000 live births. It occurs due to a deficiency of homogentisic acid dioxygenase (HGAD) which metabolizes homogentisic acid (HGA) to maleylacetoacetic acid during tyrosine metabolism. As a result of this, HGA accumulates in excess and is polymerized into blue-black pigments. The major clinical manifestations of this disorder are deposition of pigmented benzoquinone polymeric oxidation products of HGA in many tissues in the body, most commonly the joints, cardiovascular system, kidney, and skin [1].

The commonest cardiac pathology in patients with ALK is aortic stenosis (AS) [2]. Other cardiac manifestations with ALK include coronary artery disease, valvular lesions (aortic valve regurgitation, mitral valve regurgitation, tricuspid valve regurgitation), and aortic root diseases [3]. Patients with ALK may remain asymptomatic until the 6th decade. The incidence of cardiac pathology is higher in patients with ALK, as compared to the general population. We report a 70-year-old male diagnosed with ALK and AS, who underwent aortic valve and ascending aorta replacement.

Case report

A 70-year-old male, known case of ALK with AS, on regular follow-up for 4 years presented with dyspnea on exertion (grade II as per New York Heart Association classification for heart failure). He underwent total left knee replacement (TKR) surgery 10 years before and the biopsy of cartilage showed a typical pattern of ochronosis (Fig. 1). Following TKR, he had restricted domestic activities. Further, he had features of arthritis of the multiple joints, including the right knee joint, bilateral hip joints, and right shoulder joint. Laboratory investigation revealed a prolonged clotting time. Urine examination showed a significant amount of homogentisic acid. The urine turned dark on stagnation—a characteristic feature of alkaptonuria. The 24-urine analysis of homogentisic acid was 85 mg/dL (normal value, 20–30 mg/dL). Echocardiogram showed severe calcific aortic stenosis with an aortic transvalvular mean gradient of 51 mmHg (peak gradient 73 mmHg) and calculated aortic valve area of 0.9 cm². Left ventricular function was preserved with an ejection fraction of 67%. Coronary angiogram was normal, after which he was planned for elective aortic valve replacement.

Fig. 1.

Histopathology of the articular cartilage (a) shows pigment deposits (block arrows). (H&E, × 200). Methylene blue (b) highlights similar deposits

Midline sternotomy was done. The appearance of the ascending aorta was mimicking that of an intramural hematoma. It was dilated with black pigmentation on the surface. The aortic sinuses were normal. There were calcific plaques on ascending aorta and proximal aortic arch, making direct ascending aortic cannulation difficult. Hence, innominate artery was used as an arterial inflow after anastomosing it with a 7-mm vascular tube graft. Cardiopulmonary bypass was established after cannulating the right atrium. Aortotomy was done after aortic cross-clamp. There were multiple black pigments on the intima of the aorta. The aortic wall was thick with localized hematoma. The aortic valve had black pigmentation and was densely calcified causing severe aortic stenosis (Fig. 2). Both coronary ostia were normal. The aortic valve was replaced with a tilting disc valve (TTK CHVP Aortic # 23 mm). The ascending aorta, from the level of sinotubular junction to the level just below the innominate artery, was replaced with a 24-mm Dacron tube graft. The anastomosis was done using polytetrafluoroethylene (Teflon) felt on either side of the aorta. Aortic cross-clamp was removed and the patient was weaned off cardiopulmonary bypass. He had an uneventful post-operative recovery and was discharged on the 10th post-operative day. At 6 months follow-up, the patient was asymptomatic. The echocardiogram showed the normally functioning prosthetic valve with good left ventricular function. Four years after the valve replacement, the patient underwent left-sided total hip replacement.

Fig. 2.

a Ochronosis of aortic valve. b Specimen of the excised aortic valve and ascending aorta with hematoma (arrow) in the aortic wall

Discussion

ALK is an autosomal recessive disorder that is common in Slovakia, in the Dominican Republic region, and also in the German population [1]. It was first described by Garrod in 1902. Characteristic symptom triad of ALK is homogentisic aciduria, ochronosis, and arthritis. The deficiency of homogentisate 1,2-dioxygenase activity has been mapped to chromosome 3q21–q23. To date, 80 mutations of chromosome 3q21–q23 in relation with ALK have been discovered. But there is no effective therapy for this disorder, except nitisinone, which is a potent inhibitor of the second enzyme in the tyrosine catabolism [4].

The deposition of ochronotic pigment within the connective tissue of the cardiovascular system acts as a stimulant for dystrophic calcification, leading to valve stenosis or regurgitation. For unknown reasons, patients with ALK show a high affinity for aortic valve involvement, most commonly in the sixth or seventh decade of life [5]. Hence, it is imperative to follow up these patients regularly with screening echocardiograms.

ALK is a disorder that affects multiple organs. Ochronotic arthropathy is characterized by severe spine or peripheral joint (most common knee joint) pain restricting the mobility of the patient. There is also inflammation followed by swelling of the muscles and tendon attached to the joint. Multiple hypotheses like oxidized HGA deposition in the deeper layers of the articular cartilage, free radical production, decreased tissue turnover in the cartilage, and low levels of extractable matrix proteins within the joint tissue are proposed for ochronotic arthropathy [6]. These phenomena restrict the daily routine activities of these patients. Given the restricted mobility, many times the cardiac symptoms do not correlate with the severity of the valve pathology. They may be asymptomatic for a long time, even with an advanced disease. Physicians should use their judgment to correlate the echocardiogram and the clinical findings before deciding on surgery.

Arterial cannulation to establish cardiopulmonary bypass is sometimes challenging in ALK patients. Arterial calcification is a common phenomenon in ALK due to ochronotic deposition in the fibrous cap and lipid cores of atheromatous plaques [7]. A surgeon should always have a preoperative plan, if one finds calcium during the intraoperative period. The authors recommend a preoperative computerized tomography (CT) chest for better planning.

There is no consensus on the choice of the valve in ALK patients. There is a lack of evidence to prove the benefit of either the mechanical or bioprosthetic valves in these patients. Considering the pathophysiology of ALK, there are possibilities of HGA deposition and calcification over the biological tissue in the bioprosthetic valve, which may affect the longevity of the prosthesis. Hence, a few authors have suggested the use of a mechanical prosthesis in these patients, irrespective of age [8]. Considering the possibility of calcification of biological tissue, coupled with calcified access, we do not recommend transcatheter aortic valve implantation (TAVI) in these patients.

Our patient remained asymptomatic, even with severe AS, due to restricted mobility. Calcific aorta forced us to cannulate the innominate artery. Considering the long-term prognosis, we chose a mechanical valve for this elderly gentleman.

Conclusion

In conclusion, we should be aware of cardiac involvement and natural history of progression, although it is rare. Irrespective of symptoms, one should keep a close look at ALK patients for the cardiac pathology development and its progression. ALK is a systemic disease, so the surgeon should think about the probable difficulties he may counter during the surgery. To make a fixed protocol about the choice of the valve, a follow-up study is required. But considering the nature of the disease and theories proposed, the mechanical valve looks a better choice, irrespective of age.

Funding

Nil.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical statement

All procedures performed in studies involving human participants were as per with the ethical standards of the institutional and/or national research committee. This article does not contain any studies with animals performed by any of the authors.

Informed consent

Informed consent has been taken from the patient to publish this case report.

Research involving human participants/animals

Not applicable