Alkaptonuria and Ochronosis

Fig. 19.1

Pigmented patches in the sclera typical of alkaptonuric ochronosis

The diagnosis of alkaptonuria is based on the characteristic findings in urine. Alkaptonuria patients do not seek medical help due to difficulties with viewing these spots – they are without subjective complaints.

In parallel with the ocular manifestations, ochronotic changes can be found in the hearing organ. Colour changes of the auricle are visible in the 10th to 15th year of life.

Detailed histological examination of the temporal bone performed by Brunner [28] revealed accumulation of the ochronotic pigment in the bone and its membranous parts. The changes taking place in the ears are slow, and patients are alerted to the blue-grey colour of the ear by their relatives. On the cartilage, painless, hard, rough lumps can be seen firmly connected with the basis and shining through the delicate skin as dark-blue-violet colour. The first rough ridges appear on the lower arm of the anthelix and later throughout the anthelix, in the fossa triangularis, cavum conchae, cymbal and the tragus.

In advanced cases, sometimes auricle deformation can be found (Fig. 19.2). The external auditory canal is without changes; earwax is dark brown; and drum is dark, dull, often inverted, with an atypical reflex, with bluish tint, and in most cases, calcium incrustations are present. Patients may also suffer from hearing loss type hypoacusis mixta with a stronger involvement of the perceptive apparatus. Symptoms of alkaptonuria hearing organ are specific and often lead to the diagnosis of this disease.

Fig. 19.2

Ochronotic changes in the auricle

Also, changes in the skin typical of alkaptonuric ochronosis include mainly brownish or bluish pigmentation of the skin under the arm; in the face, neck and hands; and rarely on the nails. Given their visibility, they may be relevant for the early diagnosis of alkaptonuric ochronosis.

Ochronotic pigment is deposited also in the internal organs. In the region of cardiovascular organs, it is the myocardium and blood vessels. Statistically significant myocardial disorders were not found, but earlier atherosclerotic changes in the aorta were observed.

Urolithiasis was found in more than half of the patients, and rare cases of nephropathy were seen.

From a clinical point of view, the most serious process takes place in the joints and is called ochronotic arthropathy. Basically, it is a degenerative process with a known genesis and with an increased risk of disability. The basic clinical manifestation of ochronotic arthropathy from the beginning is related to the spine.

The first subjective complaints appear at the end of the third decade of life. Gender is significant with a predominance of men relative to women 2:1. Objective findings include flattening of thoracic kyphosis and lumbar lordosis and mild rigidity with a tendency to deterioration. Later, in an advanced stage, the contours of the spine worsen with irregular spinous processes and complete ankylosis of the entire lumbar and thoracic spine. The spine is rigid and irregular and the contours do not change when bending forward (Figs. 19.3, 19.4 and 19.5). Cervical spine maintains its mobility for a relatively long time despite significant skiagraphic changes. In an advanced stage, dorsal flexing and rotational movements become limited, while the head moves forward. As a result of degenerative changes of the plates in the narrowing intervertebral space, body height decreases up to 8 cm in 20 years.

Fig. 19.3

Initial stage of ochronotic changes in the spine. Flattening of physiological spinal curvatures (thoracic kyphosis and lumbar lordosis)

Fig. 19.4

The spine in ochronotic arthropathy is rigid, irregular and contours do not change in bending forward

Fig. 19.5

The spine of a patient with advanced stage of ochronotic arthropathy

Radiographic examination may reveal characteristic calcification of intervertebral discs (Fig. 19.6). Osteolytic and hyperplastic changes and secondary reactive bone formation can be found on the vertebral bodies. Osteophytes are created, sometimes even massive bone bridges of the type of ankylosing hyperostosis. Calcification of some peripheral bundles of the connective rings may be similar to pseudosyndesmotic bridges.

Fig. 19.6

Typical calcification of intervertebral discs in ochronotic arthropathy

Even in the early stages, hollow formations in the plates are formed; this is called the vacuum phenomenon. In the intervertebral joints, the space is narrowed and reactive subchondral sclerosis is present.

Sometimes, calcification is found in the ligaments between the spinous processes. Occasionally, osteoporotic vertebral fractures are found. On the other hand, thickening of bone structure is not unusual. This resembles Paget’s osteitis.

While the spine is involved in all patients with ochronotic arthropathy, peripheral joints are often, but not always, affected. Based on the analysis of 26 patients with ochronotic arthropathy, it may be noted that small joints are spared and large joints are affected in the following order: knee (64 %), shoulders (42.3 %) and hips (34.6 %) [6].

The finding in the knee is basically of arthritic nature. It differs from genuine osteoarthritis by an earlier onset (on average at the age of 39 years), faster progress and larger deformities. Hydrops occurred in 30.4 % of our patients. Based on a series of investigations, Hüttl et al. [11] have found that the synovial effusion is of a noninflammatory, irritating and degenerative nature. The effusion has a yellowish colour that remains unchanged even after prolonged standing in air, suggesting a low concentration of homogentisic acid. From the nosographic point of view, it is important to find histiocytes with brown-violet and blue-black cytoplasmic inclusions, which can be assumed to be the phagocytosed ochronotic pigment. The finding of histiocytes with pigment inclusions in the cytoplasm was described for the first time in the world literature by Hüttl et al. [11]. Radiographs in ochronotic arthropathy show similar changes as in osteoarthritis, and this is often asymmetrical. The characteristic sign is the formation of free calcified and ossified pea-sized or even larger bodies of a diverse shape. These are signs of ochronotic chondromatosis. Occasionally, narrow strips of calcified soft tissue parts of the extremities are detected that resemble Thiberge–Weissenbach syndrome. The main difference between genuine arthrosis and ochronosis of the knee is in a more rapid progression and in advanced findings in relation to the age of the patient with ochronosis.

In the shoulder joints in the early stages of ochronosis, there are painful episodes of the type of humeroscapular periarthropathy that are probably related to the deposition of pigment and calcium deposits in the rotator tendons. Gradually, the mobility gets limited due to the retraction of the joint capsule, destruction of the cartilage and the adjacent bone structures.

Radiographs of the shoulder joints show even at an early stage signs of ossifying enthesopathy. Based on analysis of 42 patients with ochronosis, Siťaj [7] reports that the calcium deposits in the shoulder rotators are present in more than 25 % of patients. In the next stage, around the 50th year of life, patients develop degenerative changes with exostosis at the inferior edge of the glenoid cavity and later with cystoid translucency, usures and destruction in the humeral head. This finding is completely different from genuine osteoarthritis and pathognomonic for ochronotic arthropathy of the shoulder.

Hip joints are affected only in later stages of ochronosis and approximately in a third of patients. The progress is faster than in osteoarthritis (OA) of the hip and results in an almost complete restriction of the mobility.

Radiographs show a severe, in some patients, destructive OA of the hip. Červeňanský et al. [10] describe ochronotic enthesopathy in the hip area and highlight the selective deposition of the ochronotic pigment in the tendons.

19.6 Coincidence of Alkaptonuric Ochronosis with Other Diseases

The metabolic disorders in ochronotic arthropathy of the spine and large joints of the limbs include osteoporosis. It is assumed that this is a secondary form of osteoporosis due to immobilisation of severely affected individuals. Barel et al. [29] describe a family affected by alkaptonuria, phenylketonuria and congenital cataract. Occasionally, alkaptonuria occurs concurrently with psoriasis. In 1955, Urbánek et al. [9] described a unique coincidence of alkaptonuric ochronosis and ankylosing spondylitis in a 51-year-old man. The patient came from a family in which four of five siblings had ochronotic arthropathy. Based on an analysis of clinical and radiographic findings in the spine, it could be assumed that ochronotic arthropathy and ankylosing spondylitis interacted. Our patient exhibited typical ochronotic changes, especially calcifications of the intervertebral discs, less marked in comparison with other patients with ochronosis in the same advanced disease stage. It may be hypothesised that the premature rigidity of the spine due to the ankylosing spondylitis caused in this patient development of ochronotic changes later in life. On the other hand, despite standard ankylosing spondylitis symptoms (affected sacroiliac joints, paraspinal ligament ossification and obliteration of intervertebral joints), the patient had disproportionately low pain throughout the course of the disease. The long-term follow-up of a large number of patients with ochronosis revealed that the relatively mild pain is characteristic for ochronotic arthropathy [7].

Japanese authors Kihara et al. [30] described the coexistence of ochronosis and rheumatoid arthritis in a 64-year-old woman. Magnetic resonance imaging of intervertebral discs revealed typical changes indicative of ochronotic arthropathy.

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