INTRODUCTION

Alkaptonuria is a hereditary metabolic disease resulted from a defective metabolism of the aromatic amino acids (MIM 203500). Due to deficiency of homogentisic acid oxidase, homogentisic acid that is a metabolic product of phenylalanine and tyrosine is partially eliminated in urine and is partially deposited in the connective tissue, especially in the cartilage, ligaments and sclera. Alkaptonuria is not associated with any symptoms; but pigment deposition in the connective tissue structures leads to several alterations, mainly of the locomotor system resulting in a clinical picture of alkaptonuric ochronosis including peripheral and axial arthropathy.

Patients with alkaptonuria are characterized by a high level of homogentisic acid in urine. The acid when oxidized especially under alkaline condition becomes dark brown and this feature is usually the first sign of the disease.

A clinical description of patients who passed urine that easily becomes dark was made by a German physician Wilhelm Adolph Scribonius in 1584 [1]. Chemical nature of the pigment was established in 1891 by M. Wolkow and W. Bauman [2]. They found that 2.5-dihydroxyphenylacetic acid is similar to gentisic acid (2.5-dihydroxybenzoic acid) and introduced the term “homogentisic acid”. Alkaptonuria was the first disorder that was revealed as a result of an inborn metabolic error. It was done by an English physician and chemist, Sir Archibald Edward Garrod, in 1902 [3]. Much later, in 1958, Bert N. La Du and co-workers [4] demonstrated a metabolic defect causing the disease. They described a lack of homogentisic acid oxydase in the liver of a patient with alkaptonuria.

The term “ochronosis” is used in two related meanings. The primary meaning refers to dark yellow pigmentation of the cartilage and/or other connective tissue structures. This pigmentation is usually caused by deposition of derivate of homogentisic acid but other chemical substances may also produce coloring of the connective tissue structures. The last condition is known as “exogenous ochronosis”. In this meaning, the term “ochronosis” is a pure morphological description of all conditions (which may be accompanied by a specific clinical picture) associated with dark pigmentation of the cartilage and other connective tissue structures. In practice, the vast majority of cases of ochronosis is produced by alkaptonuria, thus more narrowing meaning of the term “ochronosis” is equal to alkaptonuria and used to describe a clinically overt disease. The term “ochronosis” was introduced by a German pathologist Rudolf Virchow who in 1866 found microscopic appearance of the dark yellow pigment resembling ochre, i.e. iron-containing substance – one of the oldest mineral pigments used [5].

METABOLIC DEFECT AND INHERITANCE

Aromatic amino acid, phenylalanine and tyrosine are metabolized to 4-hydroxyphenylopyruvic acid and, due to subsequent oxidation, to homogentisic acid (2.5-dihydroxyphenylacetic acid). Under normal conditions, homogentisic acid is further oxidized with opening of the aromatic ring to maleylacetoacetic acid and this metabolic step is impaired in patients with alkaptonuria. The genetic defect results in a lack of active homogentisic acid oxidase (homogentisate 1.2-dioxygenase; EC 1.19.11.9); an iron-containing enzyme responsible for oxidation with “opening” of the aromatic ring. Inability to process this biochemical pathway is associated with accumulation of homogentisis acid, its excretion in urine and deposition in the connective tissue [6].

The genetic defect is located in HGO gene on arm 3q1 of the 3rd chromosome [7]. About 80 missense mutations have been described as a cause of the enzyme dysfunction [6, 8]. The disease is inherited as an autosomal recessive trait and clinical phenotype is visible in homozygotes. As a recessive disorder, it is common in offspring of consanguineous marriages. The incidence of alkaptonuria was also reported in siblings [9, 10].

Alkaptonuria is a rare disease. Its prevalence is estimated to be 1-5 cases per 1 million population [11]. The highest frequency was reported in Slovakia where prevalence 1 per 21500 inhabitants was described and, until 1980, 150 cases had been reported in the population of 3-4 millions [12-16]. In Poland, a neighbor country of Slovakia, the first case of alkaptonuria was described in 1922 [17] and, until 1980, only 39 cases had been reported [18]. Later, a few cases were described as well. About 1/3 of the cases reported in Poland referred to individuals living close to the Slovakian border [18]. High incidence was also reported in Santo Domingo [19]. The disease occurs in all races. Incidence of alkaptonuria in female and male patients remains controversial. Some studies indicate twice higher incidence in men, while other suggest equal incidence in both sexes [6].

PATHOLOGY

The polymer of homogentisis acid is deposited both, intercellularly and intracellularly. Its exact chemical nature is not defined and it is possible that it is more that polymer of homogentisic acid and further chemical modifications take place in the tissues. It has been suggested that homogentisic acid that retained in the body is oxidized to benzoquinone acetic acid under the influence of phenyl oxidase [20]. Deposition of homogentisic acid in the connective tissue seems to be reversible until the compound is polymerized, fully oxidized or potentially further modified. This is probably one of the mechanisms responsible for delayed development of clinical symptoms detected in patients with alkaptonuria. Pathological examination of tissue samples of the patients with advanced ochronosis caused by alkaptonuria revealed dark-pigmented granules visible in various tissues, including the skin, articular cartilage, intervertebral disc, tracheal and bronchial cartilage, renal tubules and islets of the pancreas. Pigment also is deposited in the arterial wall with preference to large vessels [21]. Alkaptonuric pigment granules are found in macrophages and with these cells are moved to almost all parts of the body. Macrophages with dark granules are visible in sediment of the joint fluid commonly accompanied by small dark-colored fragments of the cartilage [22]. The pigment is also deposited in a synovial membrane [23].

Serum concentration of homogentisic acid in patients with alkaptonuria is only slightly enhanced when compared to healthy individuals. It is resulted from extensive urinary excretion of the acid. Homogentisic acid in not absorbed in renal tubules and its clearance is very high, i.e. 400-500 ml/min [24].

A molecular mechanism of the connective tissue damage in patients with alkaptonuria is known only partially. It was found that homogentisic acid is an inhibitor of lysyl hydroxylase. Lysyl hydroxylase is a key enzyme for posttranslational modifications of procollagen polypeptides. Some residues of lysine within the polypeptides are transformed to hydroxylysine. Hydroxylysine is almost specific for collagen and is important for its structure. In the process of so-called collagen maturation, covalent cross-links are formed between hydroxylysine residues. The cross-links are responsible for tensile strength, attachment of carbohydrates and collagen-matrix interactions [25]. In vitro studies showed that homogentisic acid noncompetitively inhibited lysyl hydroxylase. Ascorbic acid was founded to prevent the inhibition. This mechanism has been suggested to be responsible for defective connective tissues in patients with alkaptonuria [26]. Inhibition of hydroxylysine formation can also explain predilection of alkaptonuric complication to cartilage. Different connective tissues contain various types of collagen. Collagen type I is found in dermis and type I collagen contains 5.8 hydroxylysine residues per 1000 amino acid residues. Type II collagen is the major component of cartilage and has almost three times higher content of hydroxylysine (14 residues per 1000 amino acid residues). This is probably an explanation of the profound effect of homogentisic acid on cartilage – the hydroxylysine-rich tissue. Details of this phenomenon remain unclear. Type II collagen is hydroxylysine-rich and as compared to type I collagen has greater extent of hydroxylysine glycosylation. A biological function of these glycosides remains unknown but it is suggested that they affect stabilization and integrity of the cartilage. Similarly, collagen of great vessels and other cardiovascular components (e.g. valves) contains more carbohydrates than the comparable type I collagen. Clinical symptoms are detectable after two-found decades of life.
It is believed that life-long exposure to homogentisic acid is a causative mechanism of defective collagen structure especially visible in hydroxylysine-rich collagens. An additional mechanism in form of deposition of homogentisic acid polymers and their interaction with the connective tissue matrix has been proposed to explain a structural damage and pigment deposition [25, 26].

CLINICAL PICTURE

The only visible alteration in first two decades of life of the patients with alkaptonuria is ability of urine to become dark when left for some time for oxidation. In those who had alkaline urine the dark color is visible in fresh passed urine as well. Alkaptonuria is often recognized at early days of life when diapers become dark stained. It is not a feature in patients with a high urine level of ascorbic acid or other reducing agents and in one-fourth of the patients alkaptonuria is diagnosed in adulthood.

A clinical picture of ochronosis usually develops in fourth decade of life. The clinical picture includes cartilage and skin pigmentation, ochronotic spondylosis, ochronotic peripheral arthropathy, prostatic calculi and cardiac involvement [27].

CUTANEUS AND EXTRA-ARTICULAR CARTILAGE PIGMENTATION

Dark color pigmentation of the skin of axillar, groin, over the malar area and nose is often observed in adult patients with alkaptonuria. Cartilage of the ear is altered, blue discoloration and lost of flexibility especially affect the concha and anthelix. The black cerum in the external auricular canal is found even in children with alkaptonuria. It may be associated with discoloration of the tympanic membrane and in some patients with hearing impairment [28]. Defective hearing probably results from involvement of the bones of the middle ear.

OCHRONOTIC SPONDYLOSIS

Almost all patients with alkaptonuria suffer in their fourth decade of life of severe spondylosis. The earliest involvement is found in the lumbal region and later the whole spine is affected. The symptoms are relatively mild despite significant radiographic changes. About one-tenth of the patients report pain caused by prolapsus of the nucleus pulposus. Radiculalgia is the first symptom of ochronotic spondylosis and clinically is not distinguishable from the nucleus pulpous hernation that is not associated with alkaptonuria. A few years after the first symptoms appeared, pain, stiffness or rigidity are the major complains of the patients [29]. Kyphosis and height loss are also common complaints.

Radiographic findings include calcification of the intervertebral discs with secondary narrowing of the intervertebral spaces. Splitting of the calcified disc material causes a radiographic picture of so-called “vacuum discs”. Osteophytes are usually small.

The typical for ankylosing spondylitis “bamboo” pattern of the backbone does not occur in patients with alkaptonuria. The sacroiliac joints are also not involved i.e. there is no signs of inflammation; but mild degenerative changes may appear.

OCHRONOTIC PERIPHERAL ARTHROPATHY

Peripheral arthropathy occurs in a lower number of patients with alkaptonuria than those affected by spondylosis. Large joints are often affected. Knees and shoulders are the most common location of arthropathy [30, 31]. Hips are also frequently affected [32].

Tendon involvement is relatively common in patients with ochronosis. A few cases reported tendon rupture. Filippou et al. [33] provided ultrasonographic evaluation of seven patients with alkaptonuria. They found distinctive features for tendinal involvement in the disease. They include a lack of involvement of the tendons with synovial sheaths, enthesopathy due to involvement of traction tendons at the insertion site associated with hyperechoic deposits that do not create poster shadowing (in contrast to a hydroxyapatite deposit disease) and in some cases signs of acute enthesitis. Tendon involvement is almost always symmetrical [34].
   
Articular involvement in alkaptonuria is associated with altered bone metabolism. Aliberti et al. [35] investigated 7 patients with alkaptonuria. Three of them had osteopenia and 3 others osteoporosis. Increased urinary excretion of type I collagen aminopeptide was found in the patients. It has been suggested that the patients have an increased bone resorption rate. It has been hypothesized that altered collagen metabolism and homogentisic acid polymer may affect osteocyte. In the report of the same group, medication with bisophosphate (alendronate) was found to be ineffective [36].         

OTHER CLINICAL MANIFESTATIONS

Cardiovascular involvement is common in patients with alkaptonuria but many patients have no clinically overt disease. Most described patients suffered from aortic valvular stenosis and aortic valve regurgitation [37]. Valvular and vascular abnormalities resulted from pigment accumulation in the connective tissue of the aortic – mitral and pulmonary valves [38]. Pigment accumulation is also common in the endocardium and coronary arteries. The coronary artery calcification was detected with imagine techniques in a half of the patients with alkaptonuria younger than 59 years [6]. It has been suggested that calcification is stimulated by death of pigment-laden cells [38, 39, 40]. Aortic valve stenosis was found in 3 out of 58 (about 5 per cent) of the alkaptonuric patients [6]. Clinical picture is similar to patients with aortic stenosis due to other causes but in majority of the patients the stenosis in rather mild [39, 41, 42]. In most of the reported cases, aortic valve replacement was a successful method of treatment [43].

Ocular involvement occurs in up to 70 per cent of patients. Pigment deposits in the sclera are often limited to small area between the inner or outer conthus and beginning of the cornea. This sign (so-called Osler’s sign) is sometimes helpful in early detection of the disease. Vision is not impaired in the patients [44].

Prostatic calculi are common in male patients with alkaptonuria and lead to enlargement of the prostatic gland. It is estimated that they occur in one-third of male patients [6]. The masses are detectable on rectal palpation. If the calculi and the gland enlargement are a cause of urinary retention, they should removed surgically. Sometimes they are released spontaneously. Chemically, the calculi contain pigment and calcium salts [45]. In older patients of both sexes, kidney stones are common [6].

DIAGNOSIS

Most of the patients are seeking a doctor when they or their parents discover that urine turns black. The sample of fresh urine of the patient may be normally colored unless is alkaline or contain a low level of ascorbic acid.
   
Laboratory evaluation includes addition of the Benedict’s reagent that caused the yellowish orange precipitation. It was misinterpretated as glucosuria when old laboratory tests were applied [46]. The specific determination of homogentisic acid in urine is needed for a final diagnosis. Microscopic evaluation of tissue specimens may be also helpful (e.g. synovial samples obtained at artroscopy).
   
A positive family history as well as symptoms and signs of skeletal involvement and some extroarticular features are useful in diagnostics of alkaptonuria.

DIFFERENTIAL DIAGNOSIS 

Several disorders should be considered in differential diagnosis in patients at various ages. The urine tests used for screening are non-specific and may be positive in patients after intravenous urography with some contrast media. In patients with ochronotic spondylosis, a careful diagnosis should include ankylosing spondylitis. The differences were described earlier. It should be mentioned that some families with alkaptonuria have HLA-B27 [47].
   
The cristal-deposit arthropathy, pseudogoat i.e. pyrophosphate calcium crystal deposit disease may mimic ochronotic spondylosis but in many cases both diseases coexist. Coexistence of alkaptonuria with other rheumatic disorders has been reported (e.g. with Reiter’s syndrome) [48].
   
Black pigmentation of the synovial membrane may be associated with synovitis villonodularis. Pathological investigation of the synovial membrane specimen may facilitate a differential diagnosis. In the differential diagnosis of alkaptonuria resulting in ochronosis, exoganous ochronosis should be considered. Exogenous ochronosis is a disease predominantly affecting the skin and is characterized by pigment deposition in the dermis and resulting from long-term application of topical agents. Exogenous ochronosis was first reported in 1906 [49]. A number of cases of exogenous ochronosis have been reported and the cutaneous discoloration was caused by various chemical substances. The most commonly found agents producing ochronosis are hydroquinones [50]. There are used as component of skin-lightening creams [51]. It has been suggested that a long-term application of hydroquinone leads to inhibition of homogentisic acid oxydase and mimic ochronosis resulted from inborn deficiency of the enzyme, the hereditary mechanism of alkaptonuria. At the beginning of the 20th century, carbolic acid was used for wound dressing and was a cause of exogenous ochronosis [52]. Other mechanisms of hyperpigmentation have been proposed. Determination of urinary output of homogentisic acid is the main tool for differential diagnosis of these conditions and alkaptonuria. Exogenous ochronosis was reported in patients with a long-term exposure to antimalarials (quinacrine), resorcinol, phenol, mercury or picric acid.

TREATMENT

The effective treatment of alkaptonuria, like in case of a vast majority of inborn metabolic defects, is unknown. Low aromatic amino acid diet results in a decreased urinary output of homogentisic acid but has no or very little effect on clinical conditions in patients with the overt disease. Additionally, this diet is very untasty. It is unknown if the diet is applied in early age of the patients it has any effect on development of the clinically overt disease. Most of the studies suggest prolonged administration of high doses (1.0 g daily) of ascorbic acid. This management decreases urinary excretion of homogentisic acid. In the animal model of alkaptonuria, ascorbic acid was shown to diminish the connective tissue deposits of homogentisic acid. Its clinical efficacy was not proved and seems to be ineffective in patients with the clinically overt disease [53].
   
Symptomatic treatment includes administration of nonsteroidal anti-inflammatory drugs, analgetics as well as physiotherapy and rehabilitation. Severe joint damage requires surgical joint replacement. Cardiosurgical treatment was mentioned earlier.
   
Current efforts to elaborate the novel therapeutical approaches to alkaptonuric patients include administration of nitisinone 2-(2-nitro4trifluoromethylbenzoyl)-1.3-cyclohexanedione, an inhibitor of tyrosine catabolism or enzyme replacement therapy with recombinant homogentisic acid 1.2-dioxygenase [54]. There have been reported efforts to manage patients with alkaptonuria with N-acetylcysteine and vitamin E. These compounds are believed to counteract the polymerization of the pigment, and N-acetylcysteine may neutralize metabolic products of homogentisic acid [55]. These efforts as well as a gene therapy still remain at the theoretical stage.   

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*ADRES DO KORESPONDENCJI:

Anida Grosicka
Klinika Chorób Wewnętrznych i Reumatologii
Samodzielny Publiczny Szpital Kliniczny Nr 7 SUM
40-635 Katowice, ul. Ziołowa 45/47
tel.: 32 359 82 90
fax: 32 359 82 59
e-mail: anida.grosicka@wp.pl

Pracę nadesłano: 24.08.2009 r.
Przyjęto do druku: 26.10.2009 r.