Alkaptonuria: why does urine turn black?

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Alkaptonuria is rare and causes the production of blackish urine and pigmentation of various tissues. Learn what causes it and how it affects the quality of life.

Alkaptonuria is part of a group of rare diseases called inborn errors of metabolism . It is rare and is caused by a deficiency of the homogentisic acid oxidase enzyme. It is hereditary, with a recessive Mendelian character and is transmitted from parents to children.

Clinically, it is manifested by dark urine on contact with air, dark pigmentation of tissues, and long-term joint pain, inflammation, and deformity. It usually manifests itself from hours after birth.

Homogentisic acid oxidase deficiency causes an accumulation of this acid, because it is not metabolized. The substance then enters the bloodstream and accumulates in the tissues , called ochronosis.

The amino acids involved are two

Homogentisic acid is part of the metabolism of tyrosine and phenylalanine. These are two aromatic, nonpolar, hydrophobic amino acids that are characterized by absorbing ultraviolet light at a wavelength between 200 and 360 nanometers .

Homogentisic acid is an intermediate of the phenylalanine and tyrosine degradation pathway towards the Krebs cycle. It is the substrate of the deficient enzyme and under normal conditions it is practically undetectable in blood and urine.

Read more about the Types of amino acids

Alkaptonuria is rare

Although alkaptonuria is considered one of the most common inborn errors of metabolism , it is still a very rare disease. Its worldwide prevalence is estimated at 1 case per 1,000,000 births. 

It was Scribonius in 1584 the first to describe it in a child who excreted black urine. Later, in 1850, Boedecker evidenced in this type of urine a compound that he called alcapton , which captured oxygen in the presence of reducing agents or in a medium with alkaline pH . But it was not until the findings of Wolkow and Baman that this compound was discovered to be homogentisic acid.

The joint involvement was not evidenced until 1866, when Virchow verified a dark coloration in the cartilage and joint deformation in an autopsy. When using the microscope, he detected the presence of an ocher-colored pigment. Finally, in 1958, Dru discovered that the cause of the accumulation of homogentisic acid was the absence of homogentisic acid oxidase.

Alkaptonuria is hereditary , with a recessive Mendelian character. This means that the transmission is from parents to children. For the offspring to suffer from the disease, both parents have to be asymptomatic carriers of one copy of the defective gene.

The gene in question is located on the long arm of chromosome 3 and is related to the B27 gene of the major histocompatibility complex.

What is the urine like in patients with alkaptonuria?

Homogentisic acid is a normal intermediate of phenylalanine and tyrosine metabolism that produces fumarate and acetoacetate in the liver. These compounds are part of the substrates in the metabolic pathways of energy production.

Due to enzyme deficiency, there is no metabolism of homogentisic acid and it accumulates in tissues with subsequent circulation in the blood. It is then eliminated through the urine through an energy-dependent mechanism.

Upon contact with air, oxidation from contact with reducing agents results in the typical blackish coloration.

In children, alkaptonuria usually manifests itself within hours after birth, with blackish urine staining the diaper. This is usually the only manifestation during childhood.

The pigment derived from the accumulation of homogentisic acid accumulates in collagen and cartilage, in the scleras and heart valves. The tissues that are affected turn black.

When evaluated under the light microscope, a deposition of a material in and around the cells is evident that appears ocher in color and differs from melanin only because it is resistant to hydrogen peroxide discoloration.

Dark staining in tissues is demonstrated later

Ochronotic manifestations, a product of the dark pigmentation of the tissues, occur after 30 years of life . First, there is usually spondyloarthritis , manifested by severe pain in the lumbar region, with calcifications and intervertebral ossifications.

There is also discomfort of variable and progressive intensity (product of osteoarthritis ) in the large joints (knee, hip and shoulders). Later, limitation of movements may occur due to joint deformity and degeneration.

In addition, there is darkening of the pinna, the whites of the eye, and the cornea. Earwax can also turn black and affect the tympanic membrane.

From the point of view of the heart and blood vessels, valvular calcifications may occur due to pigment deposition, leading to valve insufficiency or dilation. Although rare, kidney and prostate stones associated with pigment can be seen.

Diagnosis is by urine test

To diagnose alkaptonuria , a significant amount of homogentisic acid must be detected in the urine. Various methods are available, including gas chromatography mass spectrometry, placing a reducing agent in the urine and observing discoloration changes, or the use of 10% sodium hydroxide, silver nitrate, or Benedict’s reagent.

When there is joint symptomatology, it will be important to associate radiological imaging studies to assess the state of joint involvement. Generally, calcification and progressive ossification are evident.

At present, bone scintigraphy is included in the studies for the early detection of joint degeneration. Especially in small joints.

Joint disorders due to pathology are detected with imaging methods.

Learn about the urine test

There is no specific treatment for alkaptonuria

While it is true that synthetic replacement for the deficient enzyme would be the ideal treatment, a supplement that can do so has yet to be developed . There is no specific and effective approach.

The effects can be minimized with a diet low in phenylalanine and tyrosine. In addition, physical therapy, pain control, and, in cases of advanced joint degeneration, joint replacement are recommended.

Is vitamin C effective?

High doses of vitamin C (2-3 grams daily) were previously considered effective. This, due to its inhibition on the action of homogentisic acid in a collagen enzyme. This would decrease the accumulation of the blackish pigment in the cartilage.

However, vitamin C is a cofactor for an enzyme that causes this acid to increase. So it is not an adequate treatment.

Low protein diet is not sustainable

It is difficult to eat a low protein diet for treatment . Up to 6% of the proteins in the diet are broken down by the same metabolic pathway. In children, this affects growth.

A pathology that affects the quality of life

Alkaptonuria is a rare, hereditary, recessive disease that, although it does not affect life expectancy, does have repercussions on its quality. Its early suspicion and multidisciplinary management are important .

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