Introduction
Background
Ochronosis is the bluish black discoloration of certain tissues, such as the ear cartilage and the ocular tissue, seen with alkaptonuria, a metabolic disorder. Additionally, ochronosis can occasionally occur from exposure to various substances such as phenol, trinitrophenol, resorcinol, mercury, picric acid, benzene, hydroquinone, and antimalarials.
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.1 This deficiency results in accumulation and deposition of HGA in cartilage, causing the characteristic diffuse bluish black pigmentation. These affected connective tissue 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 noxious substances, including phenol, trinitrophenol, benzene, and hydroquinone.
Frequency
United States
Alkaptonuria is a rare autosomal recessive disease with a prevalence of 1 case per 1 million population.
International
This metabolic disorder occurs worldwide, with the highest frequency seen in the Czech Republic and Santo Domingo, in which the prevalence approaches 1 case per 25,000 inhabitants.
Mortality/Morbidity
- With the absence of homogentisic acid 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 aged 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.
Race
Alkaptonuria is seen in all races.
Sex
The incidence of alkaptonuria is equal in both sexes.
Age
Alkaptonuria is present at birth and is often diagnosed by discoloration of the diapers. Inasmuch as 25% of patients with alkaptonuria do not have the characteristic dark urine staining, many patients remain undiagnosed until adulthood.
Clinical
History
- Alkaptonuria is often recognized at birth when parents note discoloration of the urine.
- Nevertheless, many patients with this metabolic disorder are symptomless until ochronotic changes occur with bluish black pigmented patches in the sclera developing in patients aged 30-39 years. These ocular discolorations are located between the corneal margin and the inner canthus.
- The fourth decade often marks the onset of thickening and blue-black or gray-blue discoloration of the ear cartilage.
- Other body locations that frequently display the alteration in skin hue are the eyelids, the forehead, the cheeks, the axillae, the genital region, the nail beds, the buccal mucosa, the larynx, the tympanic eardrum, and the tendons (most easily demonstrated by the patient making a fist).
- Ochronotic arthropathy develops later with arthritic symptoms.
Physical
- Dark urine noted in diapers is usually the presenting manifestation of this entity.
- For those cases of alkaptonuria not diagnosed in infancy, black cerumen and axillary pigmentation may be noted before age 10 years.
- Gray-black scleral pigmentation in the configuration of small, dark rings is noted in the third decade.
- Ear cartilage alterations in the fourth decade include discoloration with a grayish blue hue, followed by structural changes with stiffness, contour irregularities, and calcification (see Media Files 1-2).
- Ochronotic discoloration can also be detected on the nasal tip, the costochondral junctions, the extensor tendons of the hands, the cheeks, the fingernails, and the buccal mucosa.
- Arthritic signs of ochronotic arthropathy develop in the third and fourth decades. Narrowing of the joint spaces and disk calcifications occur.2 Lower back, hip, and knee pain and stiffness are not uncommon.
- The clinical discoloration of the skin is a result of the formation of ochronotic pigment granules in the dermis and in the apocrine glands. Thus, the ochronotic changes of cartilaginous and tendinous structures are best appreciated in regions in which the overlying skin is of minimal thickness, such as the ears, the nasal tip, and the extensor tendons of the hands.
- Accumulation of this pigment in cardiac tissue can lead to an inflammatory reaction and progressive heart valve dysfunction.3,4
Causes
- Alkaptonuria is a genetic disorder due to a deficiency of an enzyme necessary to break down HGA.
- Ochronotic pigmentation can develop from medications. Similar skin and cartilage alterations can be induced by quinacrine administration and at sites of quinine injections.5 Quinines directly inhibit homogentisic acid oxidase. Carbolic acid topical applications to cutaneous ulcers have also induced ochronotic skin alterations.
- Exogenous ochronosis has been reported with topical applications of phenol and hydroquinones to the skin.6,7,8,9 In the case of hydroquinone, it is reported that 35% of African blacks exhibit ochronotic skin changes when using a 6-8% hydroquinone preparation over a prolonged period. Indeed, the prevalence among users of these skin lighteners has been stated to be 69% in a South African study. In African Americans, this cutaneous adverse effect of hydroquinones has been reported, even when using 2% hydroquinone products. With exogenous ochronosis, the arthropathy seen with alkaptonuria does not occur.
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References
Felbor U, Mutsch Y, Grehn F, Müller CR, Kress W. Ocular ochronosis in alkaptonuria patients carrying mutations in the homogentisate 1,2-dioxygenase gene. Br J Ophthalmol. Jun 1999;83(6):680-3. [Medline].
Gurkanlar D, Daneyemez M, Solmaz I, Temiz C. Ochronosis and lumbar disc herniation. Acta Neurochir (Wien). Aug 2006;148(8):891-4; discussion 894. [Medline].
Butany JW, Naseemuddin A, Moshkowitz Y, Nair V. Ochronosis and aortic valve stenosis. J Card Surg. Mar-Apr 2006;21(2):182-4. [Medline].
Yoshikai M, Murayama J, Yamada N. Aortic valve regurgitation in alkaptonuria. J Heart Valve Dis. Sep 2004;13(5):863-5. [Medline].
Bruce S, Tschen JA, Chow D. Exogenous ochronosis resulting from quinine injections. J Am Acad Dermatol. Aug 1986;15(2 Pt 2):357-61. [Medline].
Bongiorno MR, Arico M. Exogenous ochronosis and striae atrophicae following the use of bleaching creams. Int J Dermatol. Feb 2005;44(2):112-5. [Medline].
Findlay GH, Morrison JG, Simson IW. Exogenous ochronosis and pigmented colloid milium from hydroquinone bleaching creams. Br J Dermatol. Dec 1975;93(6):613-22. [Medline].
Hoshaw RA, Zimmerman KG, Menter A. Ochronosislike pigmentation from hydroquinone bleaching creams in American blacks. Arch Dermatol. Jan 1985;121(1):105-8. [Medline].
Zawar VP, Mhaskar ST. Exogenous ochronosis following hydroquinone for melasma. J Cosmet Dermatol. Dec 2004;3(4):234-6. [Medline].
Cortes Hernandez J, Ruiz-Oliva Ruiz F, Alonso Colmenares JI, Alvarez Ruiz S, Caton Santaren B, Alcorta Armentia MP. [Ochronotic arthropathy: the value of bone scintigraphy in alkaptonuria]. Rev Esp Med Nucl. May-Jun 2004;23(3):189-92. [Medline].
Charlin R, Barcaui CB, Kac BK, Soares DB, Rabello-Fonseca R, Azulay-Abulafia L. Hydroquinone-induced exogenous ochronosis: a report of four cases and usefulness of dermoscopy. Int J Dermatol. Jan 2008;47(1):19-23. [Medline].
Gonul M, Cakmak SK, Kilic A, Gul U, Heper AO. Pigmented coalescing papules on the dorsa of the hands: pigmented colloid milium associated with exogenous ochronosis. J Dermatol. Apr 2006;33(4):287-90. [Medline].
Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, et al. Use of nitisinone in patients with alkaptonuria. Metabolism. Jun 2005;54(6):719-28. [Medline].
Diven DG, Smith EB, Pupo RA, Lee M. Hydroquinone-induced localized exogenous ochronosis treated with dermabrasion and CO2 laser. J Dermatol Surg Oncol. Nov 1990;16(11):1018-22. [Medline].
Lang PG Jr. Probable coexisting exogenous ochronosis and mercurial pigmentation managed by dermabrasion. J Am Acad Dermatol. Nov 1988;19(5 Pt 2):942-6. [Medline].
Bellew SG, Alster TS. Treatment of exogenous ochronosis with a Q-switched alexandrite (755 nm) laser. Dermatol Surg. Apr 2004;30(4 Pt 1):555-8. [Medline].
Balaban B, Taskaynatan M, Yasar E, Tan K, Kalyon T. Ochronotic spondyloarthropathy: spinal involvement resembling ankylosing spondylitis. Clin Rheumatol. Jul 2006;25(4):598-601. [Medline].
Fernandez-Canon JM, Granadino B, Beltran-Valero de Bernabe D, Renedo M, Fernandez-Ruiz E, Penalva MA, et al. The molecular basis of alkaptonuria. Nat Genet. Sep 1996;14(1):19-24. [Medline].
Garcia SF, Egbert B, Swetter SM. Hereditary ochronosis: hyperpigmented skin overlying cartilaginous structures. Cutis. Jun 1999;63(6):337-8. [Medline].
Hardwick N, Van Gelder LW, Van der Merwe CA, Van der Merwe MP. Exogenous ochronosis: an epidemiological study. Br J Dermatol. Feb 1989;120(2):229-38. [Medline].
Huerta Brogeras M, Sanchez-Viera M. Exogenous ochronosis. J Drugs Dermatol. Jan 2006;5(1):80-1. [Medline].
Jordaan HF, Van Niekerk DJ. Transepidermal elimination in exogenous ochronosis. A report of two cases. Am J Dermatopathol. Aug 1991;13(4):418-24. [Medline].
Keller JM, Macaulay W, Nercessian OA, Jaffe IA. New developments in ochronosis: review of the literature. Rheumatol Int. Mar 2005;25(2):81-5. [Medline].
Kocyigit H, Gurgan A, Terzioglu R, Gurgan U. Clinical, radiographic and echocardiographic findings in a patient with ochronosis. Clin Rheumatol. 1998;17(5):403-6. [Medline].
Lawrence N, Bligard CA, Reed R, Perret WJ. Exogenous ochronosis in the United States. J Am Acad Dermatol. May 1988;18(5 Pt 2):1207-11. [Medline].
Mannoni A, Selvi E, Lorenzini S, Giorgi M, Airo P, Cammelli D, et al. Alkaptonuria, ochronosis, and ochronotic arthropathy. Semin Arthritis Rheum. Feb 2004;33(4):239-48. [Medline].
Martin RF, Sanchez JL, Gonzalez A, Lugo-Somolinos A, Ruiz H. Exogenous ochronosis. P R Health Sci J. Apr 1992;11(1):23-6. [Medline].
O'Brien WM. Biochemical, pathologic and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropathy. Am J Med. 1963;34:813-9.
Perrone A, Impara L, Bruni A, Primicerio P, Marini M. Radiographic and MRI findings in ochronosis. Radiol Med. Oct 2005;110(4):349-58. [Medline].
Suzuki Y, Oda K, Yoshikawa Y, Maeda Y, Suzuki T. A novel therapeutic trial of homogentisic aciduria in a murine model of alkaptonuria. J Hum Genet. 1999;44(2):79-84. [Medline].
Further Reading
Keywords
alkaptonuria, bluish black discoloration of tissue, exogenous ochronosis, exposure to hydroquinone, homogentisic acid oxidase, homogentisic acid, HGA
