Laboratory Studies

Most laboratory testing for alkaptonuria detects the alterations in the urine. Increased urinary levels of homogentisic acid (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.^{[31, 33, 34]}Bone scintigraphy can be useful in evaluation, correlation with the clinical course, and follow-up of such patients.^[35]

Chu et al point out that ankylosing spondylitis can present similarly to ochronosis on lumbar spine radiography. Both conditions may cause loss of lumbar lordosis and decreased intervertebral disc space. However, ochronosis can cause vacuum disc phenomenon with broad syndesmophytes and wafer-like disk calcification. Also, ochronosis does not typically affect the sacroiliac joint.^[36]

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% hydrogen peroxide. 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.^[37]The dermal cell infiltrate is variable but often granulomatous. Transfollicular elimination of these ochronotic fibers has been reported.

Experimental evidence has shown the presence of serum amyloid A (SAA) in several alkaptonuric chondrocytes, classifying alkaptonuria as a secondary amyloidosis. SAA in alkaptonuric chondrocytes has been shown to localize to actin, vimentin, and β-tubulin cytoskeletal proteins.^[38]

(See the images below.)

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

View Media Gallery

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

View Media Gallery

In a literature review including 11 exogenous ochronosis cases, solar elastosis was found in all cases. Histopathologic analysis using light microscopy revealed elastotic fibers transitioning to ochronotic bodies in all cases. Additionally, all ochronotic bodies were Verhoeff-van Gieson-positive.^[39]

Although both the Dogliotti and Phillips classification systems are used to grade and stage exogenous ochronosis lesions, Ramia de Cap et al assert that these systems, while useful clinically, are not suitable for histopathologic grading. This assertion is due to the lack of consistent clinical-histopathologic concordance in exogenous ochronosis.^[40]

Treatment & Management

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Media Gallery

Ochronosis revealing a perioral bluish black macular eruption after hydroquinone use.
Periorbital discoloration due to excessive use of topical bleaching preparations containing hydroquinone.
Upon microscopic examination, amber-colored, oval structures are detected in the mid-to-upper dermal tissues (hematoxylin and eosin, original magnification X40).
Upon higher magnification (of Image 3), ochronosis reveals homogenization and swelling of collagen bundles (hematoxylin and eosin, original magnification X100).

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Author

Paul N Skiba University of North Carolina at Chapel Hill School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

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.

Specialty Editor Board

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.

Chief Editor

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.

Additional Contributors

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, American Medical Association, Royal Society of Medicine, Society for Investigative Dermatology, Women's Dermatologic Society

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.