Ochronosis
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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.
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. Interleukin 6 (IL-6) has demonstrated involvement in the pigmentation process of chondrocytes. [2] 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.
United States
Alkaptonuria is a rare autosomal recessive disease with a prevalence of 1 case per 1 million population.
International
Alkaptonuria occurs worldwide, with the highest frequency seen in Slovakia and Dominican Republic, in which the prevalence approaches 1 case per 19,000 inhabitants. [3]
Alkaptonuria is seen in persons of all races.
Exogenous ochronosis is more typically seen in African and Afro-Caribbean populations due to the use of skin-bleaching products containing hydroquinone in attempts to lighten the appearance of the skin. [4]
The incidence of alkaptonuria is equal in both sexes.
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.
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. [5]
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 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.
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.
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Paul N Skiba University of North Carolina at Chapel Hill School of Medicine
Disclosure: Nothing to disclose.
Christopher Sayed, MD Clinical Assistant Professor of Dermatology, Clinician Educator, Director of Medical Student Education, Director of Hidradenitis Suppurativa Clinic, University of North Carolina at Chapel Hill School of Medicine
Christopher Sayed, MD is a member of the following medical societies: American Academy of Dermatology, American Society for Dermatologic Surgery, Medical Dermatology Society, North Carolina Dermatology Association, Society for Investigative Dermatology, Society for Pediatric Dermatology
Disclosure: Serve(d) as a speaker or a member of a speakers bureau for: Abbvie, Inc.
Craig N Burkhart, MD, MSBS Assistant Professor, Department of Dermatology, University of North Carolina at Chapel Hill School of Medicine
Craig N Burkhart, MD, MSBS is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, American Medical Association
Disclosure: Nothing to disclose.
Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology, Texas Medical Association, Association of Military Dermatologists, Texas Dermatological Society
Disclosure: Nothing to disclose.
Warren R Heymann, MD Head, Division of Dermatology, Professor, Department of Internal Medicine, Rutgers New Jersey Medical School
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Dirk M Elston, MD Professor and Chairman, Department of Dermatology and Dermatologic Surgery, Medical University of South Carolina College of Medicine
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Catharine Lisa Kauffman, MD, FACP Georgetown Dermatology and Georgetown Dermpath
Catharine Lisa Kauffman, MD, FACP is a member of the following medical societies: American Academy of Dermatology, Royal Society of Medicine, Women’s Dermatologic Society, American Medical Association, Society for Investigative Dermatology
Disclosure: Nothing to disclose.
Craig G Burkhart, MD, MPH Clinical Professor, Department of Medicine, Medical College of Ohio; Clinical Assistant Professor, Department of Medicine, Ohio University College of Osteopathic Medicine
Craig G Burkhart, MD, MPH is a member of the following medical societies: Association of Military Dermatologists, American College of Aesthetic and Cosmetic Physicians; American Society of Aesthetic/Cosmetic Physicians, Michigan Dermatological Society, Academy of Medicine of Toledo and Lucas County, Ohio Dermatological Association, American Academy of Dermatology, Ohio State Medical Association, Phi Beta Kappa
Disclosure: Nothing to disclose.
Ochronosis
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