Ochronosis is the name given to the later clinical findings of alkaptonuria. Alkaptonuria is caused by an inborn error of metabolism resulting from a defect or deficiency of the enzyme homogentisic acid oxidase. A complete lack of the enzyme in the kidneys and liver is responsible for the buildup of the homogentisic acid. Alkaptonuria is transmitted in an autosomal recessive manner. Homogentisic acid oxidase is responsible for the metabolism of homogentisic acid, which is a break- down product of the amino acids phenylalanine and tyrosine. This enzyme metabolizes homogentisic acid into maleylaceto-acetic acid, which is eventually con- verted to fumaric acid and aceto-acetic acid. When, as in alkaptonuria, the homogentisic acid oxidase enzyme is deficient, homogentisic acid accumulates in the blood and is excreted in the urine. The disease has a slow, insidious onset, and patients often present initially in young adulthood.
Clinical Findings: The first clinical sign is that of dark urine found in an affected baby’s diaper, which often causes concerned parents to seek medical advice. If left to stand for a few minutes, the urine turns dark black because of the oxidative effects of the atmosphere. The urine can be alkalinized with a strong basic solution such as sodium hydroxide; addition of the basic solution to a sample of urine promptly turns it dark black. Benedict’s reagent can also be used to test the urine of patients with alkaptonuria; when it is added, the supernatant turns dark black, and this finding is diagnostic of alkaptonuria.
As the homogentisic acid accumulates in these patients, it eventually begins depositing in skin and cartilage tissue, for which it has an affinity, becoming visibly noticeable in the fourth decade of life. The sclera is one of the first areas to be noticeably involved. A subtle brown discoloration begin to form on the lateral aspect of the sclera and continues to darken over the lifetime of the patient. The ear cartilage becomes dark brown to almost bluish due to the accumulation of the homogentisic acid. The cerumen is dark black, and evaluation of the ear may also show a darkening of the tympanic membrane and the stapes, incus, and malleus bones of the inner ear. The patient may suffer from tinnitus.
With time, the skin in various regions begins to become hyperpigmented. This occurs first and foremost in the areas with a high concentration of sweat glands. The axillae and the groin are noticeably affected. The excessive homogentisic acid is secreted in the sweat, and the pigment discolors the surrounding skin. The cheeks are also prominently affected.
The most disabling aspect of this disease is the deposition of homogentisic acid in the fibrocartilage and hyaline cartilage. This leads to severe degenerative joint disease at an early age. The pigment alters the cartilage and makes it brittle and friable. The cartilage begins to fragment and disintegrate and can get embedded in the synovial tissue, causing synovial polyps. The intervertebral disks become severely pigmented and begin to calcify because of the massive destruction of the cartilage. The disks are destroyed, causing a severe reduction in the patient’s height, as well as chronic pain and rigidity of the spine. Eventually, the heart, prostate, aorta, and kidneys all show evidence of ochronosis.
Pathogenesis: Ochronosis is the result of an autosomal recessive inherited disorder that causes the affected patient to be deficient in the enzyme homogentisic acid oxidase. This deficiency, over time, leads to the accumulation of homogentisic acid in various tissues throughout the body and the subsequent clinical manifestations.
Histology: The findings on skin biopsy are pathognomonic for ochronosis. Large ochre bodies are found within the dermis. These are obvious on low-power microscopy and can be used to confirm the diagnosis.
Treatment: No known cure is available, and there is no effective therapy. Physical therapy and joint replacement increase flexibility and range of motion and help to decrease morbidity. Some researchers advocate a diet low in phenylalanine and tyrosine, although the success of this approach is anecdotal at best. The National Institutes of Health is currently studying an inhibitor of the enzyme 4-hydroxyphenylpyruvic acid dioxygenase, which would decrease the production of homogentisic acid and theoretically help to decrease joint destruction.