Alkaptonuria (Black Urine Disease)

Alkaptonuria, also called black urine disease, alcaptonuria, and black bone disease, is one of 4 disorders originally defined as an inborn error of metabolism by Archibald Garrod in his Croonian Lectures of 1902.[1] The hallmark of the disease is passage of urine that becomes black when left standing. Garrod identified a familial pattern of inheritance and concluded that an inherited biochemical abnormality must result in the passage of an abnormal intermediate in the urine. That Garrod conceived of an intermediate is remarkable given that virtually nothing was known of serial biochemical reactions in the metabolic disposal of nutrient substances at that time.

The defect lies in the catabolic pathway of tyrosine, which contains a parahydroxylated ring structure. In a poorly understood complex reaction, the enzyme phenylpyruvic acid oxidase is thought simultaneously to move the pyruvic acid side chain, to decarboxylate it, and to add an additional hydroxyl group to the ring. The product, homogentisic acid, is actually ortho-meta- dihydroxyphenylacetic acid. A deficiency of the hepatic enzyme homogentisate 1,2-dioxygenase (HGO) forces the accumulation of homogentisic acid, which is rapidly cleared in the kidney and excreted.[2, 3]

Upon contact with air, homogentisic acid is oxidized to form a pigmentlike polymeric material responsible for the black color of standing urine. Although homogentisic acid blood levels are kept very low through rapid kidney clearance, over time homogentisic acid is deposited in cartilage throughout the body and is converted to the pigmentlike polymer through an enzyme-mediated reaction that occurs chiefly in collagenous tissues[4] . As the polymer accumulates within cartilage, a process that takes many years, the normally transparent tissues become slate blue, an effect ordinarily not seen until adulthood.

The earliest sign of the disorder is the tendency for diapers to stain black. Throughout childhood and most of early adulthood, an asymptomatic, slowly progressive deposition of pigmentlike polymer material into collagenous tissues occurs.

In the fourth decade of life, external signs of pigment deposition, called ochronosis, begin to appear. See the image below.

Upon microscopic examination, amber-colored, oval-shaped structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).

The slate blue, gray, or black discoloration of sclerae and ear cartilage is indicative of widespread staining of the body tissues, particularly cartilage. The hips, knees, and intervertebral joints are affected most commonly and show clinical symptoms resembling rheumatoid arthritis. Because of calcifications that occur in these sites, however, the radiologic picture is more consistent with osteoarthritis. Recently, ocular pigment deposition has been recognized, with adverse implications for vision.[5]  

Despite many speculations that this polymer deposition is associated with cardiac pathology, no reports of mortality directly related to the homozygous state for alkaptonuria exist. Reports exist of calcification and stenosis of the aortic annulus leading to coronary artery disease, and the risk of myocardial infarction is higher than normal in older patients with ochronosis.[6]

Molecular analysis of the HGO gene shows a wide spectrum of mutation. Although no correlation has so far been made between the molecular nature of the HGO mutation and its clinical phenotype, the wide variability of mutational phenomena could certainly help explain the clinical variability in this disease. Approximately 130 separate mutations have thus far been reported.

Frequency

United States

As Garrod suggested, alkaptonuria is an autosomal recessive genetic trait, although an autosomal dominant transmission pattern in 3 generations in a nonconsanguineous family has been reported.[7] The true frequency of alkaptonuria cannot be given with certainty for numerous reasons. These include the fact that newborn screening for alkaptonuria is much less widely practiced than that for phenylketonuria. Guidelines for phenylketonuria screening have been well established.[8]

Also, some carriers express 50% or more of normal enzyme activity and do not manifest abnormal findings even with tyrosine loading. To further complicate this picture, reports in the literature indicate wide variability in incidence, particularly where gene pools are highly restricted. In certain areas, an incidence rate as high as 1 in every 25,000 live births has been reported; worldwide it is certainly far lower.

Mortality/Morbidity

Life expectancy is normal; however, associated morbidity can be significant. Early involvement of the intervertebral discs at the thoracic and lumbar levels is very common, occurring in approximately 50% of affected individuals. Typically, significant back pain begins from age 30 years. The large joints (knee, shoulder and hip) are very frequently involved; at least half of all patients undergo joint replacement by the middle of the sixth decade of life. Achilles tendon involvement is also common and may result in tearing. Involvement of the aortic leaflets, mitral valve leaflets, or both is common, and calcifications of the coronary arteries occurs in one half of all patients prior to age 60 years.

Sex

The distribution of this disease is equal in males and females because it is an autosomal recessive or autosomal dominant trait. Males tend to have an earlier onset of arthritic symptoms with a greater degree of severity than females, although the reason for this difference is unclear.

Age

Because alkaptonuria is a genetic disorder, the deficiency of the HGO enzyme is present from conception. Clinical symptoms, aside from dark-stained diapers, are generally present only after the third decade of life.

Because alkaptonuria is usually autosomal recessive, a family pedigree, in all likelihood, reveals no other affected individuals. However, because many genetically affected individuals are asymptomatic, the low frequency of clinically affected family members may be due to a lack of ascertainment.

Despite the intrinsic biochemical defect and the expectation that all affected individuals should excrete urine that becomes black when left standing, a significant number of people with alkaptonuria do not present with this clinical finding.

The most common history is one of arthritic symptoms confined chiefly to the spine, hips, and knees. Virtually all people with alkaptonuria eventually experience arthritis. Onset of thoracic back pain, lumbar back pain, or both around age 30 years is frequent.

Slate blue or gray discoloration may be found in the sclerae or ear cartilage.

Calcifications may be palpable in the discolored areas, particularly in the cartilage of the ear.

Joint mobility diminishes, as in osteoarthritis. Ankylosis may be present. Spontaneous fusion of one or more discs may occur, with consequent diminished spinal flexion. Joint effusions, particularly in the knee are common and range of motion may be significantly diminished.

Signs of aortic or mitral valvulitis may be present.

Inability to convert homogentisic acid to maleylacetoacetic acid results in accumulation of the former. Homogentisic acid is subsequently converted to benzoquinone acetic acid and spontaneously polymerized. Deposition of the polymer in association with cartilage is the initiating pathophysiologic cause of the arthritis.[25]

Although unproven, the deposition of polymer is assumed to also cause an inflammatory response that results in calcium deposition in affected joints.

Exogenous agents including quinacrine (Atabrine), carbolic acid, and hydroquinone have been reported to cause an ochronotic picture without the joint disease. All have been reversible.

In patients with alkaptonuria, homogentisic acid can be identified in urine using gas chromatography – mass spectroscopy. Spectrophotometric quantitation shows 2 orders of magnitude elevations above normal.

Because many patients present without dark urine, looking for homogentisate in all patients with radiographic evidence of osteoarthritis may be advisable.

After DNA extraction from whole blood, screening for mutations can be performed with polymerase chain reaction (PCR) technique.

Spinal radiography reveals disk degeneration combined with dense calcification, particularly in the lumbar area.

Chest radiography is advised to assess for possible involvement of aortic or mitral valves.

In affected individuals older than 55 years, CT scanning may provide evidence of coronary artery calcifications.

Electrocardiography may be advisable, with particular attention directed at any signs of myocardial insufficiency.

Other studies and procedures should be directed at the joint disease itself.

Joint replacements may become necessary in severely affected larger joints.

In association with the gross visual finding of black-stained cartilage in various areas of the body (eg, larynx, costochondral junctions, trachea), microscopic examination reveals pigment deposition within and outside cells in these tissues.

No specific stain is available to distinguish homogentisate-derived pigment from melanin, and the 2 compounds have similar solubility characteristics.

In infancy, a history of dark-stained diapers should alert the physician to alkaptonuria.[9]

Infants, young children, and asymptomatic young adults can be evaluated with simple urine testing on an outpatient basis.

Medical therapy is used to ameliorate the rate of pigment deposition. This minimizes articular and cardiovascular complications in later life.

Reduction of phenylalanine and tyrosine has reportedly reduced homogentisic acid excretion. Whether a mild dietary restriction from early in life would avoid or minimize later complications is not known, but such an approach is reasonable.

Vitamin C, as much as 1 g/d, is recommended for older children and adults. The mild antioxidant nature of ascorbic acid helps to retard the process of conversion of homogentisate to the polymeric material that is deposited in cartilaginous tissues.

More recently, use of nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic acid, has been reported.[10, 11]  Urinary homogentisate excretion was markedly reduced, and safety of prolonged use is no longer an open question.

Older individuals may require removal of lumbar discs with fusion.

Hip, shoulder, or knee joint replacement may be necessary.

Consultations may include the following:

• Biochemical geneticist

• Neurosurgeon

• Orthopedist

• Cardiologist (older patients)

Reduction of phenylalanine and tyrosine reportedly reduced homogentisic acid excretion in the urine of a child. In an adult, a similar restriction reportedly had no effect on excretion of the abnormal metabolite. Whether a mild dietary restriction from early in life would avoid or minimize later complications is not known, but such an approach is reasonable.

Vitamin C, as much as 1 g/d, is recommended for older children and adults.

Nitisinone is now known to be useful in managing alkaptonuria. Vitamin C, as much as 1 g/d, is also recommended for older children and adults.[10, 11, 22]

Class Summary

Organic substances required by the body in small amounts for various metabolic processes.

Ascorbic acid (Cecon, Cevalin, Cevi-Bid, Ce-Vi-Sol)

The mild antioxidant nature of ascorbic acid helps to retard the process of conversion of homogentisate to the polymeric material that is deposited in cartilaginous tissues.

Class Summary

Nitisinone, a tyrosine degradation inhibitor, has been used experimentally.

Nitisinone (Orfadin)

This compound has, until recently seen very restricted use in experimental treatment for alkaptonuria. Tyrosine degradation inhibitor. Inhibits 4-hydroxyphenylpyruvate dioxygenase, which mediates formation of homogentisic acid. Its clinical use has now been shown to be safe and effective.

Carefully monitor diet with periodic measurement of plasma amino acid levels to avoid phenylalanine deficiency.

If treatment for alkaptonuria is successful, the patient does not need to be admitted to the hospital.

Medications are not needed, although large doses of supplemental vitamin C may be beneficial. Administration of daily nitinosone should be considered. 

Transfer is not required if appropriate outpatient consultation and follow-up are obtained.

High-protein diets should be avoided.

No exercise restriction is necessary in the absence of cardiovascular disease.

Potential complications include the following:

• Calcification of the ear cartilage

• Calcified lumbar discs

• Severe arthritis

• Ankylosis

• Aortic or mitral valvulitis

Life expectancy is normal.

Risk of myocardial infarction later in life is increased.

Family members should be referred for genetic counseling.

The need for rigorous follow-up with a biochemical geneticist should be emphasized.

Patients and family members should be counseled regarding a likely decreased quality of life.

For excellent patient education resources, see eMedicineHealth's patient education article Arthritis.