Alkaptonuria-Associated Aortic Stenosis

Lok, Zoe Shin Yee; Goldstein, Jacob; Smith, Julian Anderson

doi:10.1111/jocs.12129

Cited by 21 publications

(16 citation statements)

References 20 publications

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“…Results were very reproducible and revealed that pigmented areas were composed by C, O, N, S, Na, and variable amount of Ca. Sulphur is an element never reported before in cardiac valve tissue, and its constant presence in the pigment is probably due to the ability of HGA oxidized to BQA, to form adducts with protein thiols [6]. The white concretions (Figure 2(a)B) contained P and Ca that indicated the presence of hydroxyapatite.…”

Section: Resultsmentioning

confidence: 91%

“…Mechanical stress, one of the typical functional features of heart valve, may be a linker between amyloid and ochronotic pigment copresence, since it has been reported to be responsible for both amyloid deposition [20, 24, 25] and ochronotic pigment deposition in AKU [6, 9]. Mechanical stress in heart valves has been positively related to oxidation of lipoproteins inducing calcification in pathologies [20, 25, 28, 34].…”

Section: Discussionmentioning

confidence: 99%

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Amyloidosis, Inflammation, and Oxidative Stress in the Heart of an Alkaptonuric Patient

Millucci

Ghezzi

Paccagnini

et al. 2014

Mediators of Inflammation

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Background. Alkaptonuria, a rare autosomal recessive metabolic disorder caused by deficiency in homogentisate 1,2-dioxygenase activity, leads to accumulation of oxidised homogentisic acid in cartilage and collagenous structures present in all organs and tissues, especially joints and heart, causing a pigmentation called ochronosis. A secondary amyloidosis is associated with AKU. Here we report a study of an aortic valve from an AKU patient. Results. Congo Red birefringence, Th-T fluorescence, and biochemical assays demonstrated the presence of SAA-amyloid deposits in AKU stenotic aortic valve. Light and electron microscopy assessed the colocalization of ochronotic pigment and SAA-amyloid, the presence of calcified areas in the valve. Immunofluorescence detected lipid peroxidation of the tissue and lymphocyte/macrophage infiltration causing inflammation. High SAA plasma levels and proinflammatory cytokines levels comparable to those from rheumatoid arthritis patients were found in AKU patient. Conclusions. SAA-amyloidosis was present in the aortic valve from an AKU patient and colocalized with ochronotic pigment as well as with tissue calcification, lipid oxidation, macrophages infiltration, cell death, and tissue degeneration. A local HGD expression in human cardiac tissue has also been ascertained suggesting a consequent local production of ochronotic pigment in AKU heart.

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Section: Resultsmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

Amyloidosis, Inflammation, and Oxidative Stress in the Heart of an Alkaptonuric Patient

Millucci

Ghezzi

Paccagnini

et al. 2014

Mediators of Inflammation

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“…The ochronotic chondrocyte pigmentation of a mouse model was also shown to follow an age-related pattern with the first signs of pigmentation restricted to the pericellular matrix surrounding individual chondrocytes, followed by eventual progression to the intracellular compartment (Preston et al 2014). The cartilaginous tissues and bone seem to be particularly susceptible resulting in widespread arthritis and joint destruction (Keller et al 2005) as well as deterioration of cardiac valves (Lok et al 2013). In fact a lack of HGD activity in human cardiac tissue was suggested as the cause of localised production of ochronotic pigment in AKU heart (Lok et al 2013).…”

Section: Pigmentation In Aku: the Nature Of The Pigmentmentioning

confidence: 99%

“…The cartilaginous tissues and bone seem to be particularly susceptible resulting in widespread arthritis and joint destruction (Keller et al 2005) as well as deterioration of cardiac valves (Lok et al 2013). In fact a lack of HGD activity in human cardiac tissue was suggested as the cause of localised production of ochronotic pigment in AKU heart (Lok et al 2013). It could be that other tissues affected by the disease with an enzyme defect have similar increased HGA and pigment production contributing to the induction of ochronotic arthropathy (Laschi et al 2012).…”

Section: Pigmentation In Aku: the Nature Of The Pigmentmentioning

confidence: 99%

The Pigment in Alkaptonuria Relationship to Melanin and Other Coloured Substances: A Review of Metabolism, Composition and Chemical Analysis

et al. 2015

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The pigments found in plants, animals and humic substances are well described and classified. In humans considerable progress has been made with the main pigment melanin in defining its biochemistry, the different types and function. However, analytical techniques to show these differences in vivo are still not readily available. NMR and IR spectroscopy are relatively insensitive and reveal only major structural differences. Techniques utilising MS are useful in determining elemental content but require further studies to optimise conditions for accurate mass analysis. How the components may be structurally organised seems to be the most problematic with scanning TEM and the improved FTIR of use in this respect. As regards understanding the nature of the pigment related to HGA seen in patients with Alkaptonuria (AKU), it is still thought of as a melaninlike pigment simply because of its colour and likewise thought to be a polymer of undetermined size. It is important that detailed analysis be carried out to define more accurately this pigment. However, observations suggest it to be the same as the HGA-derived pigment, pyomelanin, produced by bacteria and containing both quinone and phenolic groups. The interesting developments in alkaptonuria will be to understand how such a polymer can cause such profound collagen and connective tissue damage and how best to reverse this process.

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“…An increased prevalence of aortic valve disease, and in particular aortic stenosis, is seen in patients with alkaptonuria compared to the general population [6]. In the Cardiovascular Health Study, which looked at 5621 patients aged 65 or older, 1.8% were found to have aortic stenosis [7].…”

Section: Discussionmentioning

confidence: 99%

Black Heart at Surgery - Primary Diagnosis of Alkaptonuria at Surgery

Karavaggelis¹,

Young²,

Attia³

2017

JCCR

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Alkaptonuria is a rare genetic disorder of tyrosine catabolism in which homogentisic acid accumulates leading to ochronotic deposition in connective tissue. This has widespread effects including degenerative arthritis and, more rarely, cardiovascular manifestations, the most common of which is aortic stenosis. We present a 66-year old patient in whom we diagnosed alkaptonuria during an aortic valve replacement for symptomatic aortic stenosis. We conducted a world literature review to examine the evidence for the prevalence of aortic valve disease and cardiac involvement in alkaptonuria. We discuss the pathogenesis of aortic valve ochronosis. Keywords:

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Alkaptonuria-Associated Aortic Stenosis

Cited by 21 publications

References 20 publications

Amyloidosis, Inflammation, and Oxidative Stress in the Heart of an Alkaptonuric Patient

Amyloidosis, Inflammation, and Oxidative Stress in the Heart of an Alkaptonuric Patient

The Pigment in Alkaptonuria Relationship to Melanin and Other Coloured Substances: A Review of Metabolism, Composition and Chemical Analysis

Black Heart at Surgery - Primary Diagnosis of Alkaptonuria at Surgery

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