Practice Essentials
Ochronosis is the bluish-black discoloration of certain tissues, such as the ear cartilage and the ocular tissue, seen with alkaptonuria, a metabolic disorder. Alkaptonuria is a rare genetic disorder in which there is a deficiency of the enzyme homogentisic acid oxidase, resulting in the accumulation of homogentisic acid and a characteristic blue-black discoloration of the skin and cartilage, called ochronosis. Exogenous ochronosis can occasionally occur from exposure to various substances such as phenol, trinitrophenol, resorcinol, mercury, picric acid, benzene, hydroquinone, and antimalarials.
Diagnostics
Dermoscopy has proved useful in exogenous ochronosis. In addition to melasma findings, dermoscopy reveals amorphous, densely pigmented structures obliterating some follicular openings and multiple thin, short, arciform structures. [1, 2]
Synovial fluid examination of affected joints shows characteristic frequent pigmented fibrillar connective tissue, which are golden-brown with microscopy, while being black on gross examination. [3]
Arthroscopy can be used in diagnosing cases of ochronotic arthropathy. [4]
Dark urine in diapers is usually the presenting manifestation. For cases not diagnosed in infancy, black cerumen and axillary pigmentation may be noted before age 10 years. In the third decade, gray-black scleral pigmentation is noted in the configuration of small, dark rings. In the fourth decade, ear cartilage alterations include discoloration with a grayish-blue hue.
Treatments
With exogenous cutaneous ochronosis induced by topical hydroquinones, carbon dioxide lasers and dermabrasion have been reported to be helpful. [5, 6] Reports have described effective therapy with the Q-switched alexandrite 755-nm laser. [7]
Arthroscopy has been found to be effective in alleviating joint pain and improving mobility in cases of ochronotic arthropathy. [4]
Ranganath et al have shown that nitisinone 2 mg daily and 10 mg daily are beneficial in patients with alkaptonuria, with 10 mg displaying a greater decrease in HGA. The authors note that a diet lower in protein would likely improve safety with the higher dose. Nitisinone 10 mg was approved by the European Medicines Agency for adults with alkaptonuria in 2020. [8] Nitisinone is approved in the United States for the treatment of children with tyrosinemia type I. It acts by inhibiting the enzyme 4-hydroxyphenyl pyruvic acid and therefore can decrease formation of HGA. [9]
Patient Education
Patients with alkaptonuria should be informed that they will have a normal life span, despite pigmentary alterations and arthritis that materialize in mid life. Patients should also be aware that they will need cardiovascular follow-up care in their later years. Activities are restricted in adult life because of arthritic complaints. Physical or occupational therapy may be indicated in the individual management of joint pain and in order to help with muscle strength and flexibility.
Pathophysiology
Ochronosis was defined by Virchow who histologically described the connective tissue in alkaptonuria, given the cartilage's ochre, or yellow, hue under the microscope.
Alkaptonuria is a rare autosomal recessive metabolic disorder caused by deficiency of homogentisic acid oxidase, the only enzyme capable of catabolizing homogentisic acid (HGA). Alkaptonuria features a defect in the biochemical pathway by which phenylalanine and tyrosine are normally degraded into fumaric and acetoacetic acid. The genetic defect is autosomal recessive and is mapped to the HGO gene on arm 3q1, and 18 genetic missense mutations are known to cause homogentisic acid oxidase aberrations. [10] This deficiency results in accumulation and deposition of HGA in cartilage, causing the characteristic diffuse bluish-black pigmentation. Interleukin 6 (IL-6) has demonstrated involvement in the pigmentation process of chondrocytes. [11] These affected connective tissues become weak and brittle with time, leading to chronic inflammation, degeneration, and osteoarthritis.
Exogenous ochronosis, in which bluish-black pigmentation of cartilage is noted iatrogenically by exogenous agents, has been seen after exposure to antimalarials and noxious substances, including phenol, trinitrophenol, benzene, hydroquinone, mercury, resorcinol, and picric acid. Note that localized argyria may be mistaken for exogenous ochronosis. [12]
Epidemiology
Alkaptonuria is a rare autosomal recessive disease with a prevalence of 1 case per 1 million population. Alkaptonuria occurs worldwide, with the highest frequency seen in Slovakia and Dominican Republic, in which the prevalence approaches 1 case per 19,000 inhabitants. [13] While alkaptonuria is seen in persons of all races, exogenous ochronosis is more typically seen in African and Afro-Caribbean populations because of the use of skin-bleaching products containing hydroquinone in attempts to lighten the appearance of the skin. [14]
The incidence of alkaptonuria is equal in males and females. Alkaptonuria is present at birth and is often diagnosed by discoloration of the diapers. Up to 25% of patients with alkaptonuria do not have the characteristic dark urine staining, and many patients remain undiagnosed until adulthood.
Prognosis
Patients with alkaptonuria can expect a normal life span; nevertheless, the complications of debilitating arthritis, cardiovascular compromise, and ochronotic skin alterations will occur. Additionally, chronic kidney disease affects the natural history of the disease by accelerating the onset of major complications. [15]
Mortality/morbidity
With the absence of homogentisic acid (HGA) oxidase in liver and kidney cells, HGA accumulates. The black urine of patients with alkaptonuria results from renal excretion of HGA, while ochronotic pigment is a sequela of HGA accumulation in the connective tissues of individuals who are affected.
In alkaptonuria, the accumulation of HGA inhibits collagen cross-linking by affecting a crucial enzyme in collagen synthesis, leading to a diminution of structural collagen integrity. This results in ochronotic arthropathy, which occurs in men in their fourth and fifth decades; women develop similar complications in their sixth decade. The larger joints are most affected with early calcification, narrowing, and collapse of the intervertebral discs. In addition to joint disease, reports suggest an increased incidence of cardiovascular disease due to cartilaginous changes of vessel walls.
Homogentisic acid oxidase requires atmospheric oxygen, ferrous ion, and sulfhydryl groups for normal function, and the enzyme is inhibited by quinones. HGA is colorless in solution but darkens on exposure to air, especially in the presence of alkali. Individuals with acidic urine may not demonstrate the very dark-colored urine characteristic of this condition.
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Ochronosis revealing a perioral bluish black macular eruption after hydroquinone use.
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Periorbital discoloration due to excessive use of topical bleaching preparations containing hydroquinone.
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Upon microscopic examination, amber-colored, oval structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).
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Upon higher magnification (of Image 3), ochronosis reveals homogenization and swelling of collagen bundles (hematoxylin and eosin, original magnification X100).
