As it can be seen in Table 9.1, out of 21 alkaptonuric patients diagnosed in the first decade, ochronosis was detected only in one of them (eye involvement), i.e. 4.7 %. In the second decade, we did not find any ochronotic patient; in the third, fourth and fifth decades, the percentage of ochronosis markedly increased reaching the highest value of 62.5 %, and later on in the sixth, seventh and eighth decades, it gradually decreased to the value of 25 %. If any conclusions can be made from this material, it could be deduced that the critical age for ochronosis development is the fifth decade and in alkaptonuric patients passing to elder age groups, ochronosis does not occur or tissue pigmentation is so limited that it is not clinically manifested. Microscopic or discrete changes detectable by histochemical methods cannot be ruled out in these cases of alkaptonuria.

As it was mentioned before, deposition of homogentisic acid and its polymer – ochronotic pigment –results not only in vital staining of so-called bradytrophic tissues but also in large regressive changes that are particularly marked in articular cartilaginous and periarticular tissues (tendons).

Boedecker (1859) was the first one to point out the relationship between alkaptonuria, ochronosis and articular signs. Gross and Allard (1907) called these changes improperly as ‘alkaptonuric arthritis’. In ochronotic arthropathy, all vitally important articular structures are affected. Procházka and Hněvkovský (1953) even found the impregnation in subchondral layers of the joints. Vascular system nourishing the bone ends up in this zone, and lymphatic sinuses take over the nutrients supply. The authors hypothesised that the principal injury of cartilaginous tissue in ochronosis is the blockade of lymphatic sinuses resulting in change of concentration of hydrogen ions. These layers, where the bone neogenesis takes place, are extraordinarily sensitive to pH changes. The support for this concept is the presence of ochronotic changes on vascular intima. The changes are most pronounced in terminal arterioles, thus affecting local metabolic processes. We also have to assume successive exposure of other layers of cartilage to homogentisic acid and its more or less polymerised derivatives (see Chap. 27 the ‘Case Report’).

Homogentisic acid causes the loss of cartilage elasticity and its successive hardening. More recent histochemical observations demonstrate that proteoglycans together with their glycosaminoglycans (previously called mucopolysaccharides) that bind a large amount of water with their negative charge are responsible for cartilage elasticity (Knudson and Knudson 2001). Apparent loss of proteoglycans can be seen in degenerative changes of articular cartilage. It is anticipated that homogentisic acid and its polymers disrupt the matrix of connective tissue by unfavourable impact on proteoglycans (mucopolysaccharide complex of the matrix). However, it seems that ochronotic injury is not caused by shredding of superficial layers to fibres as seen in cartilages affected by arthrosis, but it probably causes its glassiness and fragility. Cartilage can easily fragment to small pieces that are often similar to pins with the development of so-called chondrosis dissecans. Besides these changes, disorders of cartilage continuity and cracks reaching to bone with various depths occur. Secondary changes in the bone similar to arthrosis arise on this basis.