Alcaptonuria and Ochronotic Arthropathy

What is Alcaptonuria and Ochronotics Arthropathy?

Alcaptonuria is a rare hereditary disease associated with impaired amino acid metabolism of tyrosine and phenylalanine, leading to the accumulation in the body of an intermediate product of the metabolism of these amino acids – homogentisic acid (alkapton).

Alcapton is excreted in the urine, which, when standing in air and oxidation of alcapton, turns black. The disease was first described by Scribonius, and M. Volkov and E. Bauman isolated homogentisic acid crystals from the urine of patients. Alkaptonuria is distributed mainly in Czechoslovakia, often affects men. The frequency of the disease is 0.01 per 10 thousand people.

Pathogenesis during Alcaptonuria and Oronothic Arthropathy

According to modern data, the development of alkaptonuria is associated with a congenital deficiency of the homogentisinase enzyme (homogenous acid oxidase), as a result of which the breakdown of tyrosine and phenylalanine does not occur in their final products, fumaric and acetoacetic acids, but stops at the level of homogentisic acid, which accumulates in the organism. It has been proven that homogentisinase is a highly specific enzyme that catalyzes the oxidation of homogentisic acid, and is found in the liver and kidneys.

Alcaptonuria refers to hereditary diseases with an autosomal recessive mode of inheritance of a homogentisinase defect. R. Pieter described a family, thirteen members of which in the four generations studied suffered from alkaptonuria.

Pathological anatomy
The accumulation of homogentisic acid in the body is the deposition of its oxidation product – an ochronotics pigment in the connective tissue: in the cartilages of the spine and large joints, cartilage of the auricle, nose, larynx, skin, sclera of the eyes, vascular epithelium, in the glands – thyroid, pancreas, prostate, in the epididymis, as well as in the myocardium and heart valves.

As a result of pigment impregnation, these tissues acquire a dark brown color (ocronoz) with subsequent deposition of calcium in these places and ossification. Skin coloration is explained by the deposition of pigment in the epithelium of skin vessels, in the sweat glands and reticuloendothelial cells.

Alcaptone deposition, and then calcium in the cartilage of the joints and pozononochiky: changes and development of deforming ocherotic osteoarthritis (or achrotic arthropathy) and spondylosis. The deposition of pigment in the cartilage of the ear gives the auricle a blue color, and the subsequent calcification leads to its compaction and coarsening. In some cases, myocardial infarction and the appearance of systolic murmur as a result of the impregnation of the heart valves by the pigment may result from the deposition of pigment in the tissues and vessels of the heart.

Thus, the disease is characterized by three main features: alkaptonuria, ocronosis and arthropathy. However, these signs appear non-simultaneous: Alcaptonuria – the presence of homogentisic acid – exists from birth, chronosis – dark dyeing of tissues – develops slowly and becomes pronounced by the age of 30, arthropathy appears after 30-40 years of life.

Symptoms of Alcaptonuria and Ochronotic Arthropathy

On examination of the patient, gray-brown pigmentation and thickening of the skin of the face, especially on the back of the nose, around the eyes and lips, as well as the dark coloring of the skin folds on the neck, abdomen, palms, in the armpits and the groin are visible. Characterized by a gray-blue color and density of auricles. On the sclera of the eye, focal brown pigmentation in the form of triangular spots or dots is detected. Pigment deposition can also be on the conjunctiva.

The pigmentation and consolidation of tissues that appeared by the age of 30 gradually increased. An early sign of ochronosis is diffuse deposition of pigment in the cartilage of the larynx and their subsequent degeneration, which is clinically manifested by pain when swallowing and palpation of the larynx, and radiographically darkening in the laryngeal area.

Diffuse pigmentation and calcification of the heart valves, endocardium, myocardium, aortic intima and vascular endothelium of the heart leads to the development of atherosclerosis, aortic sclerosis, myocardial fibrosis and sclerotic mitral and aortic valve defects with an appropriate clinical and X-ray picture. Men often form stones in the prostate gland (calculous prostatitis). Less commonly, stones form in the kidneys. Clinically, kidney damage may manifest as albuminuria or pyelonephritis.

The lesion of the joints, Alcaptonuric, or ochronotics arthropathy with a chronic progressive course, is one of the main clinical manifestations of the disease. Spine and large joints of the extremities are affected. First of all, the lumbar spine is affected, and then the thoracic spine, where the phenomena of deforming spondylosis slowly develop. The cervical region is usually not affected. Gradually, dull pains and a feeling of stiffness in the spine appear, the pains then increase and radiate to the extremities and intercostal spaces. Movement and palpation painful. The lumbar lordosis becomes smoothed, leading to a decrease in patient growth. Gradually limited movement in the spine and, finally, comes the complete loss of mobility in the lumbar and thoracic regions.

In some cases, the first clinical manifestation of ocronotic spondylosis may be acute “disc syndrome”, which develops as a result of a rupture of intervertebral cartilage with the formation of a hernia of an intervertebral disk.

A few years after the spinal cord lesion, pain in the knee, and then shoulder and hip joints. Pain may be accompanied by a slight swelling (reactive synovitis), a crunch, flexion contractures in these joints. Due to the fragility of the articular cartilage, even a small injury of the joint (especially the knee) can cause a fracture or even a fracture of the cartilage with the separation of its fragments and the occurrence of reactive synovitis. The presence of free foreign bodies (cartilage fragments) in the joint cavity periodically causes the phenomenon of “joint blockade”. A picture of severe arthrosis gradually develops with destruction of cartilage, osteophytosis, deformity of the joints and restriction of their mobility, but without the development of ankylosis. At the same time, ossification of the soft periarticular tissues is observed. A very characteristic is a lesion of the pubic articulation, where pain (sometimes sharp) and pain on palpation occur.

Diagnosis of Alcaptonuria and Ochronotic Arthropathy

Ochronotic spondylosis has the following symptoms: calcification of intervertebral discs (chondrocalcinosis of discs), narrowing of intervertebral fissures, osteosclerosis of vertebral bodies on the border with discs, development of small osteophytes with subsequent ankylosis (complete fusion of vertebral bodies). The narrowing of the gap, osteosclerosis and calcification are also observed in the pubic articulation.

It should be emphasized that, in contrast to Bechterew’s disease, this disease never exhibits ossification of the ligaments of the spine, lesions of the apophyseal and sacroiliac joints. Radiographs of large peripheral joints show signs of deforming arthrosis, narrowing of the joint cracks, osteosclerosis, osteophytes, free osteochondral bodies (usually under the patella or in the popliteal fossa), as well as ossification of cartilage, soft periarticular tissues, and sometimes adjacent tendons.

Body temperature, blood tests are normal. Overall condition is satisfactory. However, due to the progression of mobility impairment, the patient gradually becomes invalid.

Diagnosis and differential diagnosis
For the diagnosis of alkaptonuria, the patient’s indication of darkening of the urine when standing on the air, as well as the appearance of black spots on linen, characteristic pigmentation and thickening of the skin of the face, neck, abdomen, palms, underarms, auricles is of most importance. The presence of chronic fever / kenya of the joints and the spine with progressive deterioration of their function and a characteristic X-ray picture (cartilage calcification) is also stinging.

Some diagnostic value is the study of synovial fluid, which in Alcaptonuria has features. It is non-inflammatory, has normal cytosis with a predominance of mononuclears, but contains dark particles, similar in expression to A. Gordon, to black pepper. These particles of an ocronotic pigment are also contained in the cytoplasm of phagocytic cells of the synovial fluid. When microscopy can also be detected fragments of pigmented cartilage, which, apparently, the basis for the formation of osteochondral bodies. Calcium pyrophosphate may be present in synovial effusion.

The disease should be differentiated from ankylosing spondylitis and primary deforming spondylosis. It should be borne in mind that, in contrast to Bechterew’s disease, when ocherotic spondylosis occurs, lesions of the cervical spine and the sacroiliac joint are observed, and radiography shows calcification of the discs and cartilage of the peripheral joints in the absence of calcification of the ligaments.

From the deforming spondylosis, the ocronotic spondylosis is distinguished by the calcification of the discs, the lesion of the symphysis, and especially by the tendency to ankylosing.

Treatment of Alcaptonuria and Ochronotic Arthropathy

Etiological therapy (replacement of the missing enzyme) does not yet exist. Some authors have noted the desirability of eating protein-poor food, which may limit the formation of homogentisic acid.

It is advisable to assign patients large doses of ascorbic cysts (5-6 g daily), which as an enzyme takes part in the process of decomposition of tyrosine. To reduce pain and improve joint mobility, pain relievers are used, as well as balneophysiotherapy therapies — general radon baths, paraffin or mud applications, etc. With significant joint deformities, orthopedic surgical correction is necessary.

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