eMedicine Specialties > Dermatology > Metabolic Diseases

Ochronosis

Craig G Burkhart, MD, MPH, Clinical Professor, Department of Medicine, Section of Dermatology, Medical College of Ohio at Toledo; Clinical Assistant Professor, Department of Dermatology, Ohio University School of Medicine
Craig N Burkhart, MD, MSBS, Assistant Professor, Department of Dermatology, University of North Carolina at Chapel Hill

Updated: Dec 30, 2008

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.

Differential Diagnoses

Argyria
Arsenical Keratosis

Workup

Laboratory Studies

Most laboratory testing for alkaptonuria detects the alterations in the urine. Increased urinary levels of HGA are characteristic of this metabolic disorder.
- Elevated levels of HGA in the urine, blood, and other tissues can be determined by specific enzymatic and colorimetric tests, direct spectrophotometric methods, high-performance liquid chromatographic testing, and molecular techniques.
- Other simple urinary studies include darkening of urine with the addition of sodium hydroxide, black reaction with FeCl₃, and blackening of photographic emulsion paper with alkali added to urine.

Imaging Studies

In patients with ochronotic arthropathy, radiography and MRI help identify characteristic and diagnostic features, including articular space narrowing up to osseous ankylosis, calcifications, osteophytosis, and reactive sclerosis of the articular surfaces.⁹ Bone scintigraphy can be useful in evaluation, correlation with the clinical course, and follow-up of such patients.¹⁰

Procedures

Dermoscopy has proved useful in exogenous ochronosis. In addition to melasma findings, dermoscopy reveals amorphous densely pigmented structures obliterating some follicular openings.¹¹

Histologic Findings

Skin biopsy samples with hematoxylin and eosin staining reveal yellowish brown pigmented bodies in the dermis that represent altered widened elastic fibers, as well as in macrophages, endothelial cells, apocrine glands, and epidermal basement membranes. The deposits do not lose their pigmentation after 3 days in 10% H₂ O₂. Furthermore, the ochronotic pigment reacts with all routine stains for melanin. Such deposits can also be seen in cartilage and elastic tissue.

Exogenous ochronosis reveals ochronotic collagen fibers leading to the formation of ochronotic colloid milium.¹² The dermal cell infiltrate is variable but often granulomatous. Transfollicular elimination of these ochronotic fibers has been reported.

Treatment

Medical Care

Although no present medical treatment is available for alkaptonuria, genetic advances offer hope that corrective measures are forthcoming. Some have advocated diets low in tyrosine and phenylalanine, thereby reducing the toxic byproduct HGA. Additionally, a diet high in vitamin C might prevent oxidation of homogentisic acid. The clinical effects of dietary changes has been minimal.

One possible hope is that nitisinone proves effective.¹³ The US Food and Drug Administration has approved this drug for the treatment of tyrosinemia type 1. It significantly lowers the urinary excretion of HGA by inhibiting 4-hydrophenylpyruvate dioxygenase and, thoracally, would reduce HGA accumulation. Testing presently is assessing safety and long-term results.

Ochronotic arthropathy is treated with physiotherapy, analgesia, rest, and prosthetic joint replacement when necessary.

Surgical Care

With exogenous cutaneous ochronosis induced by topical hydroquinones, carbon dioxide lasers and dermabrasion have been reported to be helpful.^14,15 Reports have described effective therapy with the Q-switched alexandrite 755-nm laser.¹⁶

Consultations

Consultations with a rheumatologist for the arthropathies that develop should be considered.
An expert in medical genetics may be of assistance in screening families for this autosomal recessive metabolic disorder.
A cardiac assessment and follow-up care are needed upon entering the fourth decade of life.

Activity

Activities are restricted in adult life because of arthritic complaints.

Medication

At the present state of knowledge, no medical therapy for ochronosis and alkaptonuria is available. The US Food and Drug Administration has approved this drug for the treatment of tyrosinemia type 1. It significantly lowers the urinary excretion of HGA by inhibiting 4-hydrophenylpyruvate dioxygenase and, thoracally, would reduce HGA accumulation. Testing presently is assessing safety and long-term results.

Follow-up

Further Outpatient Care

Patients need cardiovascular follow-up care upon entering their fourth decade of life.

Complications

Complications of alkaptonuria include arthropathy and possible cardiovascular disease (see Mortality/Morbidity).

Prognosis

Patients with alkaptonuria can expect a normal life span; nevertheless, the complications of debilitating arthritis, cardiovascular compromise, and ochronotic skin alterations will occur.

Patient Education

Patients with alkaptonuria need to know that they will have a normal life span, despite pigmentary alterations and arthritis that materialize in mid life.
Patients need cardiovascular follow-up care in their later years.

Multimedia

Media file 1: Ochronosis revealing a perioral bluish black macular eruption after hydroquinone use.

Media file 2: Periorbital discoloration due to excessive use of topical bleaching preparations containing hydroquinone.

Media file 3: Upon microscopic examination, amber=-colored, oval-shaped structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).

Media file 4: Upon higher magnification (of Image 3), ochronosis reveals homogenization and swelling of collagen bundles (hematoxylin and eosin, original magnification X100).

References

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Keywords

alkaptonuria, bluish black discoloration of tissue, exogenous ochronosis, exposure to hydroquinone, homogentisic acid oxidase, homogentisic acid, HGA

Contributor Information and Disclosures

Author

Craig G Burkhart, MD, MPH, Clinical Professor, Department of Medicine, Section of Dermatology, Medical College of Ohio at Toledo; Clinical Assistant Professor, Department of Dermatology, Ohio University School of Medicine
Craig G Burkhart, MD, MPH is a member of the following medical societies: American Academy of Dermatology, Ohio State Medical Association, and Phi Beta Kappa
Disclosure: Nothing to disclose.

Coauthor(s)

Craig N Burkhart, MD, MSBS, Assistant Professor, Department of Dermatology, University of North Carolina at Chapel Hill
Craig N Burkhart, MD, MSBS is a member of the following medical societies: American Academy of Dermatology, American College of Physicians, and American Medical Association
Disclosure: Nothing to disclose.

Medical Editor

C Lisa Kauffman, MD, FACP, Professor, Chief, Division of Dermatology, Departments of Medicine and Pathology, Georgetown University Medical Center
C Lisa Kauffman, MD, FACP is a member of the following medical societies: American Academy of Dermatology, American Medical Association, Royal Society of Medicine, Society for Investigative Dermatology, and Women's Dermatologic Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University 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, Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Warren R Heymann, MD, Head, Division of Dermatology, Professor, Department of Internal Medicine, University of Medicine and Dentistry of New Jersey
Warren R Heymann, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Society for Investigative Dermatology
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

Further Reading