Ochronosis or alkaptonuria is a rare, autosomal recessive metabolic disease where the enzyme homogentisic acid 1,2-dioxygenase is congenitally absent.
This enzyme is necessary in the oxidation of phenylalanine and tyrosine.
As a result of this defect homogentisic acid, which is normally produced during the metabolism of the two amino-acids, cannot be further metabolized.
It therefore accumulates in the serum.
It is massively excreted in the urine and as it is oxidized, the urine turns dark, a feature termed alkaptonuria.
Tissue pigmentation called ochronosis is due to the presence and the chemical binding in the connective tissue of oxidized and polymerised products of homogentisic acid.
Pigment deposits lead to joint destruction, renal stone formation and cardiac valvulopathy.
Accumulation of homogentisic acid, in eye, skin, cartilage and several other connective tissues leads to a black pigmentation of the affected tissues.
Pathology of Alkaptonuria -
Excessive homogentisic acid is associated with the following important features:
- Urine excretion of homogentisic acid is very high.
Characteristically, the excess homogentisic acid means the patient passes dark urine, which on standing turns black.
This is a feature present from birth.
Black urine Diagram- Pigment present in various organs.
The urine turns black if allowed to stand or is alkalinized as a result of formation of polymerization products of homogentisic acid also known as alkapton.
- Ocular ochronosis. The ochronotic pigment can be found in the sclera, the conjunctiva, and the limbic cornea.
Vision is usually not affected.
Skin and connective tissue
Diagram showing irregular shaped deposit in the dermis.
Clinically, in ochronosis, there is blue-black pigmentation of the ears, nose, cheeks, neck, dorsum of the hands, and palmoplantar region resulting from binding of homogentisic acid to connective tissue and cartilage.
Yellow brown pigment is deposited in the collagen containing tissue.
Microscopically, in the early stage there is basophilia of the collagen fiber in the upper dermis.
In the later stage sharp, well-defined cresentic or banana-shaped pigmented fibres are present.
Pigmented deposits are also present in the dermis, within the macrophages, in the endothelial cells of blood vessels and basement membrane of sweat glands.
Arthropathy associated with deposition in articular cartilage. The pigmented cartilage loses resilience and is readily eroded.
Ochronotic arthropathy is present in about one third of the patients with alkaptonuria.
The large joints (knee, shoulder and hips), as well as the spinal column, are affected.
Cardiovascular disease : Heart and aorta :
The pathogenesis of cardiovascular ochronosis is unclear, but is probably related to the extensive extracellular deposits of ochronotic pigment in the cardiac tissue.
Light microscopy and ultrastructural studies of the aortic valve show intracellular and extracellular deposits of ochronotic pigment.
Large deposits of extracellular ochronotic pigment is associated with areas of valvular calcification.
Electron microscopic study of the aorta show ochronotic pigment in the macrophages and smooth-muscle cells.
Collection of extracellular ochronotic pigment in the intima and media are often present near the necrotic cells.
Changes in the renal biopsy - Renal biopsy tissues show diffuse chronic tubulo-interstitial disease characterized by widespread tubular atrophy, interstitial fibrosis, and a moderate degree of inflammation.
Many tubular cells contain brown, coarsely granular ochronotic pigment and a few pigment casts are present in the lumina.
Similar deposits are also noted the interstitium and within histiocytes.
Ultrastructural studies of the glomeruli reveal small sparse ochronotic pigment deposits in the visceral and parietal epithelial cells, mesangial cells, and rare extracellular and basement membrane deposits.
The tubulointerstitial changes are varied: There is atrophy and dilatation of tubules, varying degrees of lysosomal ochronotic pigment and degeneration of tubular cells, casts containing ochronotic pigment with crystalline material, histiocytes distended with ochronotic pigment, and free interstitial pigment deposition.
Renal failure is rare and usually occurs in the later stages of the disease.
Other systemic features include:
Stones (renal, prostatic, salivary, gall bladder), osteopenia/ fractures, ruptures of tendons/ muscle/ ligaments, respiratory compromise and hearing loss.
Black coloured urinary calculus has been extracted from the urethra.
Fatal cases are rare, and death often results from kidney or cardiac complications.
Skin signs are the most important feature of endogenous ochronosis and must alert the clinician to look for involvement of vital organs.
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