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Background

Ochronosis or alkaptonuria is a metabolic disorder in which homogentisic acid oxidase is absent. Therefore, homogentisic acid accumulates in cartilage and connective tissues. This deposition of dark pigment is known as ochronosis.

OUTLINE

Epidemiology  
Disease Associations  
Pathogenesis  
Laboratory/Radiologic/
Other Diagnostic Testing
 
Gross Appearance and Clinical Variants  
Histopathological Features and Variants  
Special Stains/
Immunohistochemistry/
Electron Microscopy
 
Differential Diagnosis  
Prognosis  
Treatment  
Commonly Used Terms  
Internet Links  

 

EPIDEMIOLOGY CHARACTERIZATION
SYNONYMS Alkaptonuria
INCIDENCE/
PREVALENCE
 
AGE  
SEX  
GEOGRAPHY  
EPIDEMIOLOGIC ASSOCIATIONS  
Exogenous ochronosis: an epidemiological study.

Hardwick N, Van Gelder LW, Van der Merwe CA, Van der Merwe MP.

Department of Dermatology, University of Pretoria, South Africa.

Br J Dermatol. 1989 Feb;120(2):229-38. Abstract quote  

A survey was conducted to investigate the relationship between exogenous ochronosis and the use of skin lightening preparations amongst black individuals attending general outpatient departments in two South African hospitals.

In the sample, 15% of males and 42% of females were found to have exogenous ochronosis. The prevalence amongst users of skin lighteners was 69%. The main demographic associations with ochronosis were an inverse relationship to education, and predominance of the female sex. Clinical and behavioural aspects were also recorded.

Even products limited to 2% hydroquinone or less, and combined with a sunscreen, were found to cause ochronosis.

 

DISEASE ASSOCIATIONS CHARACTERIZATION

 

PATHOGENESIS CHARACTERIZATION
MUTATIONS IN THE HOMOGENTISATE 1,2-DIOXYGENASE GENE  
Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations.

Uyguner O, Goicoechea de Jorge E, Cefle A, Baykal T, Kayserili H, Cefle K, Demirkol M, Yuksel-Apak M, Rodriguez de Cordoba S, Wollnik B.

Division of Medical Genetics, Child Health Institute, Istanbul University, Turkey.
J Inherit Metab Dis. 2003;26(1):17-23. Abstract quote  

Alkaptonuria (AKU) is a rare metabolic disorder of phenylalanine catabolism that is inherited as an autosomal recessive trait. AKU is caused by loss-of-function mutations in the homogentisate 1,2-dioxygenase (HGO) gene. The deficiency of homogentisate 1,2-dioxygenase activity causes homogentisic aciduria, ochronosis and arthritis.

We present the first molecular study of the HGO gene in Turkish AKU patients. Seven unrelated AKU families from different regions in Turkey were analysed. Patients in three families were homozygous for the R58fs mutation; another three families were homozygous for the R225H mutation; and one family was homozygous for the G270R mutation. Analysis of nine intragenic HGO polymorphisms showed that the R58fs, R225H and G270R Turkish AKU mutations are associated with specific HGO haplotypes. The comparison with previously reported haplotypes associated with these mutations from other populations revealed that the R225H is a recurrent mutation in Turkey, whereas G270R most likely has a Slovak origin.

Most interestingly, these analyses showed that the Turkish R58fs mutation shares an HGO haplotype with the R58fs mutation found in Finland, Slovakia and India, suggesting that R58fs is an old AKU mutation that probably originated in central Asia and spread throughout Europe and Anatolia during human migrations.
GENERAL  
Bone metabolism in ochronotic patients.

Aliberti G, Pulignano I, Schiappoli A, Minisola S, Romagnoli E, Proietta M.

Dipartimento di Scienze Cliniche, Universita di Roma La Sapienza, Rome, Italy.

J Intern Med. 2003 Sep;254(3):296-300. Abstract quote  

We investigated skeletal involvement in five male and two female patients with ochronosis, aged 26-82 years. The main parameters of mineral metabolism, together with biochemical markers of bone resorption (urinary N-telopeptides of type I collagen) and formation (serum bone isoenzyme of alkaline phosphatase and serum osteocalcin) were evaluated. In the same subjects lumbar spine and femoral bone mineral density (BMD) were also measured by dual energy X-ray absorptiometry.

All patients but the younger 26-year-old patient had lower than normal bone mass at femoral neck and total hip, showing marked osteopenia in three cases and osteoporosis in the remaining three cases. However, at lumbar spine BMD measurement provided spuriously overestimated results, because of intervertebral disc calcification and osteophyte formation. As far as biochemical markers of bone turnover are concerned, the most relevant finding was the increased N-telopeptides of type I collagen urinary excretion.

Our results suggest that ochronosis may be associated with increased bone resorption rate leading to an accelerated bone loss. A role of the homogentisic acid polymer deposit in bone matrix and cells, possibly with osteocyte damage and interference in collagen metabolism, might be hypothesized.

 

LABORATORY/
RADIOLOGIC/
OTHER TESTS

CHARACTERIZATION
RADIOLOGIC  
Radiographic and MRI findings in ochronosis.

Perrone A, Impara L, Bruni A, Primicerio P, Marini M.

Dipartimento di Scienze Radiologiche , Radiologia Centrale B, Universita degli Studi di Roma La Sapienza - Roma.

Radiol Med (Torino). 2005 Oct;110(4):349-358. Abstract quote  

PURPOSE: Ochronotic arthropathy is the articular manifestation of alkaptonuria, a rare hereditary metabolic disease that leads to the deposition of homogentisic acid particularly in the joints where it causes articular degeneration and inflammation. We studied the radiological patterns of the disorder using both traditional X-rays both MRI and comparing the results obtained with the two techniques.

MATERIALS AND METHODS: The study included five patients (4 males, 1 female, mean age 51 years); we studied the most frequently affected sites, the knee, the shoulder and the spine. As regards the conventional study we used a radiographic score which considered the state of the articular space and the presence of calcifications. MRI of the peripheral joints was performed on the most symptomatic site or, if asymptomatic, on the most severely affected site as established by radiography; in all cases T1- and T2-weighted sequences in the axial, sagittal and coronal planes were acquired.

RESULTS: Both the X-ray and MRI study revealed the typical alterations of ochronosis in the cases with a known diagnosis: articular space narrowing up to osseous ankylosis, calcifications, osteophytosis, reactive sclerosis of the articular surfaces; MRI was however more accurate in identifying the alterations and revealing lesions not visible at conventional radiology, such as ligament lesions. In the case of newly diagnosed ochronotic arthropathy MRI proved valuable for its ability to detect alterations that are poorly appreciable at conventional radiology.

CONCLUSIONS: Modern diagnostic imaging, above all MRI, allowed us to identify the peculiar characteristic features of ochronosis and is fundamental both for the diagnosis and for differentiating ochronosis from other articular disorders.
LABORATORY MARKERS  

 

GROSS APPEARANCE/
CLINICAL VARIANTS
CHARACTERIZATION
GENERAL  
VARIANTS  
SKIN-EXOGENOUS  
Exogenous ochronosis.

Huerta Brogeras M, Sanchez-Viera M.

Department of Dermatology University Hospital Gregorio Maranon, Madrid.

J Drugs Dermatol. 2006 Jan;5(1):80-1. Abstract quote  

We describe a case of a 70-year-old woman who had been using a skin-lightening cream containing hydroquinone for a previous diagnosis of melasma.

She presented a hyperpigmentation predominantly on her cheeks and eyebrows.

The biopsy showed deposition of yellow-brown globules in the dermis. A diagnosis of exogenous ochronosis was made. An attempt of treatment using a Q-switched Nd:YAG laser has been initiated recently.
Exogenous ochronosis and striae atrophicae following the use of bleaching creams.

Bongiorno MR, Arico M.

Department of Dermatology, University of Palermo, Palermo, Italy.
Int J Dermatol. 2005 Feb;44(2):112-5. Abstract quote  

Exogenous ochronosis is a paradoxical hyper-pigmentation of the skin caused by the long-term use of hydroquinone-containing bleaching creams. Ochronosis is an uncommon condition characterized by yellow-brown pigmented deposits in the dermis.

We report two cases of exogenous ochronosis in two female patients of the sub-Saharan African population. The lesions were characterized by an asymptomatic hyper-pigmentation of the face with gradually progressive blue-black macular patches, and in case no. 2, in addition to dyschromic lesions, striae atrophicae were present.

This phenomenon is the outcome of the use of skin care products containing high concentrations of hydroquinone- and glucocorticoid-based products, and, in addition, certain modalities in the use of bleaching products are likely to facilitate complications.
Exogenous ochronosis. An update on clinical features, causative agents and treatment options.

Levin CY, Maibach H.

University of California, San Francisco Medical Center, Department of Dermatology, San Francisco, California, USA.


Am J Clin Dermatol. 2001;2(4):213-7. Abstract quote  

Exogenous ochronosis is clinically and histologically similar to its endogenous counterpart; however, it exhibits no systemic effects and is not an inherited disorder.

It is characterized by an asymptomatic hyperpigmentation of the face, sides and back of the neck, back, and extensor surfaces of the extremities. The associated ochronotic discoloration most commonly results from use of products containing hydroquinone. It also occurs following use of antimalarials and products containing resorcinol, phenol, mercury or picric acid. The etiology of hydroquinone-induced hyperpigmentation in exogenous ochronosis remains speculative.

The majority of patients with this condition are Black, but it has been reported to occur in Hispanics and Caucasians. Exogenous ochronosis is prevalent among South African Blacks, but is believed relatively uncommon within the US. The reasons for this phenomenon are not clear, but it could be a result of the use of skin care products containing resorcinol in combination with hydroquinone or the use of hydroquinone in a hydroalcoholic lotion.

Treatment of this condition is difficult. The offending agent must be avoided, but improvement occurs only slowly. A number of topical agents have been studied as have dermabrasion and the use of lasers. Controlled studies in larger numbers of patients are require to determine the true efficacy of newer treatments.
Idiopathic pigmentation of the hands. Professional exogenous ochronosis? A new entity?

Dupre A, Bonafe JL, Viraben R, Arquie MT.


Arch Dermatol Res. 1979 Aug;266(1):1-9. Abstract quote  

A case of ochronosis-like pigmentation of the hands is described.

The following criteria were fulfilled: (1) presence of blue to black spots confined to the hands: (2) pitch-black macroscopic appearance of the biopsy specimen; (3) abundance of granular material in the whole connective structures on microscopic examination of an unstained specimen just mounted on a slide; (4) numerous pigmented granules in the elastic and collagen fibers: (5) no family history, abnormal coloration of the urine, taking of drugs, or rheumatism; (6) onset in a manual worker exposed to benzenic substances.

This seems to be a new entity, probably a variant of exogenous ochronosis produced by professional contacts with some agents and perhaps a professional benzenic ochronosis.
BODY SITES-NON CUTANEOUS  
ARTHROPATHY/
ARTHRITIS
 
Ochronotic arthropathy: disappearance of alkaptonuria after liver transplantation for hepatitis B-related cirrhosis.

Kobak AC, Oder G, Kobak S, Argin M, Inal V.

Department of Medicine, Section of Gastroenterology and Hepatology, Ege University, School of Medicine, Bornova, Izmir, Turkey.
J Clin Rheumatol. 2005 Dec;11(6):323-5. Abstract quote  

The deficiency of homogentisic acid oxidase, an enzyme that is mainly found in hepatocytes, is associated with alkaptonuria and ochronosis.

We report a patient with clinical and radiologic findings of ochronotic arthropathy in whom alkaptonuria disappeared and the progressive course of the disease stopped after liver transplantation for hepatitis B-related cirrhosis.
Ochronotic spondyloarthropathy: spinal involvement resembling ankylosing spondylitis.

Balaban B, Taskaynatan M, Yasar E, Tan K, Kalyon T.

Department of Physical Medicine and Rehabilitation, School of Medicine, Gulhane Military Medical Academy, Gata, 06018, Ankara, Turkey
Clin Rheumatol. 2005 Nov 3;:1-4 [Epub ahead of print] Abstract quote  

Ochronotic spondyloarthropathy is a rare metabolic disease with the musculoskeletal manifestations of alkaptonuria. Ochronotic arthropathy patients may have spinal abnormalities similar to ankylosing spondylitis (AS).

The proof of sacroiliac involvement or bamboo spine appearance is not sufficient either for diagnosis of ankylosing spondilitis or exclusion of ochronosis.

In this report, the case of a 54-year-old woman having ochronosis, with clinically more recognizable axial arthropathy resembling AS, is presented, and the history, clinical presentation, diagnostic techniques, and distinctive diagnosis are reviewed.
Ochronotic arthritis: case reports and review of the literature.

Cetinus E, Cever I, Kural C, Erturk H, Akyildiz M.

Faculty of Medicine, Department of Orthopedics, University of Kahramanmaras Sutcu Imam, Kahramanmaras, 46050, Turkey.

Rheumatol Int. 2005 Aug;25(6):465-8. Epub 2004 Dec 3. Abstract quote  

Alkoptunuria is an inherited autosomal recessive metabolic disorder which is caused by the lack of homogentisic acid-oxidase enzyme. It is associated with various systemic abnormalities and related to the deposition of homogentisic acid pigment in connective tissues. These pigmentary changes are termed "ochronosis".

We describe two patients with ochronotic arthritis who presented with advanced degenerative changes in the lumbo-sacral spine, knee and hip. The literature, differential diagnosis and management of this rare condition are reviewed in this article.

Alkaptonuria, ochronosis, and ochronotic arthropathy.

Mannoni A, Selvi E, Lorenzini S, Giorgi M, Airo P, Cammelli D, Andreotti L, Marcolongo R, Porfirio B.

Rheumatology Unit, Azienda Sanitaria di Firenze, Florence, Italy.

Semin Arthritis Rheum. 2004 Feb;33(4):239-48. Abstract quote  

OBJECTIVES: To describe the clinical presentation and course of a relatively large group of Italian adult patients screened for mutation of the homogentisate dioxygenase gene causing alkaptonuria (AKU) and ochronosis, and to review typical and atypical facets of this condition.

METHODS: We reviewed the medical records of 9 patients affected by ochronotic arthropathy who were observed in our institutions between 1979 and 2001. All patients were diagnosed as having AKU through a rapid urine test with alkali. Mutation screening was performed by single-strand conformation analysis of all homogentisate dioxygenase exons, followed by sequencing of altered conformers.

RESULTS: Our 9 cases had similar clinical features and they reflected those described in the literature: a progressive degenerative arthropathy mainly affecting axial and weight-bearing joints associated with extraarticular manifestation. Musculoskeletal symptoms began in most of our patients around the age of 30 years with back pain and stiffness: involvement of the large peripheral joints usually occurred several years after spinal changes. Ochronotic peripheral arthropathy generally was degenerative, but joint inflammation was observed in some cases; this could be attributed to an inflammatory reaction of the ochronotic shard in the synovial membrane.

CONCLUSIONS: Ochronosis is a model of arthropathy with known etiologic factors. Over time, AKU, the genetically determined metabolic defect, leads to the accumulation of pigment and the development of this crippling condition. Most of the clinical findings may be explained by inhibition of collagen crosslinks, but some require additional interpretation. For example, inflammatory features of the ochronotic joint only occur in a minority of cases, and may be attributable to ochronotic shards. Further studies are needed to establish the genotype-phenotype correlation to identify mutations that are predictive of severe disease. For this purpose, the Italian Study Group on Alkaptonuria (www.dfc.unifi.it/aku) is enrolling affected patients in an on-line database to characterize the molecular defects and their relationship to clinical data.
EYE  
Ocular ochronosis: A case report and clinical findings.

Soker Cakmak S, Cevik R, Aksunger A, Unlu K, Ava S.

Department of Ophthalmology, University of Dicle, School of Medicine, Diyarbakir, Turkey.

Acta Ophthalmol Scand. 2002 Jun;80(3):340-2. Abstract quote  

PURPOSE: To report a rare case of bilateral asymmetrical melanin-like pigments found in the cornea, conjunctiva and sclera.

METHODS: Systemic investigation with clinical and laboratory analysis.

RESULTS: The case was diagnosed as one of alkaptonuria and ocular ochronosis.
HEART  
Cardiac ochronosis: valvular heart disease with dark green discoloration of the leaflets.

Erek E, Casselman FR, Vanermen H.

Department of Cardiovascular and Thoracic Surgery, Onze-Lieve-Vrouwziekenhuis Clinic, 9300 Aalst, Belgium.

Tex Heart Inst J. 2004;31(4):445-7. Abstract quote  

We report the case of 67-year-old woman who underwent aortic valve replacement and mitral valve repair due to ochronotic valvular disease (alkaptonuria), which was diagnosed incidentally during cardiac surgery.
Aortic valve regurgitation in alkaptonuria.

Yoshikai M, Murayama J, Yamada N.

Department of Cardiovascular Surgery, Shin-Koga Hospital, Kurume City, Fukuoka, Japan.
J Heart Valve Dis. 2004 Sep;13(5):863-5. Abstract quote  

Aortic valve lesions associated with alkaptonuria tend mostly to be due to aortic valve stenosis, while aortic valve regurgitation is only rarely observed.

Herein, a case is reported of severe aortic valve regurgitation and a fibrous strand in a patient with alkaptonuria. A 65-year-old male, with a history of inferior myocardial infarction, presented with symptoms of congestive heart failure.

Alkaptonuria was diagnosed based on urine coloration, skin pigmentation and ochronotic arthropathy in the vertebrae and hip. Grade IV aortic valve regurgitation with mild aortic valve stenosis and occlusive disease in the right coronary artery indicated a need for aortic valve replacement and coronary artery bypass grafting. Sclerotic change in the cusps, and shrinkage of the non-coronary cusp, impeded normal coaptation of the aortic valve, and the left-coronary cusp also had a fibrous strand suspending the free margin of the cusp from the aortic wall just above the commissure.

The sclerotic change in the cusps, and shrinkage of the non-coronary cusp, appeared to be the causative lesion of aortic valve regurgitation, implying that cardiovascular ochronosis may cause aortic valve regurgitation.

 

HISTOLOGICAL TYPES CHARACTERIZATION
GENERAL  
SKIN  
Transepidermal elimination in exogenous ochronosis. A report of two cases.

Jordaan HF, Van Niekerk DJ.

Department of Dermatology, University of Stellenbosch, Tygerberg, Republic of South Africa.

Am J Dermatopathol. 1991 Aug;13(4):418-24. Abstract quote  

Exogenous ochronosis is caused by the long-term application of skin-lightening creams containing hydroquinone. This irreversible disfiguring cosmetic problem assumes epidemic proportions in South African blacks.

Mild ochronosis is characterized clinically by coarsening and darkening of the skin; severe ochronosis, by coalescing, caviar-like black papules and atrophy. Histology shows ochronotic collagen fibers with eventual formation of ochronotic colloid milium. A variable cellular infiltrate, which may be granulomatous, is present.

We describe two patients with severe exogenous ochronosis who developed superimposed papular lesions. Histology in both cases showed transfollicular elimination of ochronotic fibers. In one patient, gross epidermal hyperplasia, a dense lichenoid infiltrate, and partial destruction of ochronotic fibers accompanied the process of elimination (cell-rich type). In the other, concomitant epidermal hyperplasia and a cellular infiltrate were absent (cell-poor type). Further studies are needed to prove or disprove the existence of such a proposed subdivision.

Transepidermal elimination in exogenous ochronosis has been mentioned in a previous report, but to our knowledge this is the first detailed documentation of this phenomenon. The clinical and histopathological spectrum of exogenous ochronosis is thus expanded.
Actinic granuloma-like change in exogenous ochronosis: case report.

Jordaan HF, Mulligan RP.

Department of Dermatology, Tygerberg Hospital, Private Bag, South Africa.

J Cutan Pathol. 1990 Aug;17(4):236-40. Abstract quote  

Exogenous ochronosis is caused by the longterm application of skin-lightening creams containing hydroquinone. This irreversible disfiguring cosmetic problem assumes epidemic proportions in South African blacks.

Mild ochronosis is characterized clinically by coarsening and darkening of the skin and severe ochronosis by coalescing, caviar-like black papules and atrophy. Histology shows ochronotic collagen fibres with eventual formation of ochronotic colloid milium. A variable cellular infiltrate, which may be granulomatous, is present.

We describe a 39-year-old black woman with severe exogenous ochronosis who developed superimposed annular lesions with granulomatous histology bearing great resemblance to lesions of actinic granuloma.
Granulomatous ochronosis -- a cosmetic-induced skin disorder in Blacks.

Dogliotti M, Leibowitz M.

S Afr Med J. 1979 Nov 3;56(19):757-60. Abstract quote  

More skin eruptions than previously are appearing in Blacks after the application of a variety of topical cosmetics. Clinical and histological descriptions of these conditions are reviewed and classified.

Four cases of sarcoid-like foreign-body granulomas are reported. The stricter control of cosmetics is recommended.

 

SPECIAL STAINS/
IMMUNOPEROXIDASE/
OTHER
CHARACTERIZATION
SPECIAL STAINS  
IMMUNOPEROXIDASE  
ELECTRON MICROSCOPY  

 

DIFFERENTIAL DIAGNOSIS KEY DIFFERENTIATING FEATURES
ARGYRIA  
Localized argyria with pseudo-ochronosis.

Robinson-Bostom L, Pomerantz D, Wilkel C, Mader R, Lerner L, Dufresne R, Flotte T.

Department of Dermatology, Brown University School of Medicine/Rhode Island Hospital, Providence, RI 02903, USA.
J Am Acad Dermatol. 2002 Feb;46(2):222-7. Abstract quote  

BACKGROUND: Localized argyria is uncommon and presents clinically as asymptomatic slate gray macules or blue macules resembling blue nevi. Its histopathologic features are usually similar to those of generalized argyria in which silver granules are found most commonly around the eccrine glands, in the walls of blood vessels, and along elastic fibers. Ochre swollen homogenized collagen bundles resembling ochronosis have not been previously described.

OBJECTIVE: The purpose of this study is to report a series of 5 patients with localized argyria with the histologic feature of "pseudo-ochronosis." In one patient, biopsy was performed on 2 distinct lesions.

METHODS: All patients underwent skin biopsies for light microscopy and darkfield microscopy. In two patients, the biopsy specimens were analyzed with a mass spectrophotometer; scanning electron microscopy and energy-dispersive x-ray analysis were performed. In one patient, the biopsy specimen was decolorized with 1% potassium ferricyanide in 20% sodium thiosulfate.

RESULTS: All 5 patients presented with the typical clinical and histologic features of localized argyria. Ochre swollen and homogenized collagen bundles were seen in all cases. In addition, light microscopy in 4 cases revealed an ellipsoid black globule within a zone of collagen degeneration.

CONCLUSION: The histologic features of localized argyria include swollen and homogenized collagen bundles resembling ochronosis, "pseudo-ochronosis," which may be more common than previously recognized.
MINOCYCLINE  

Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain.

Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA.

Section on Human Biochemical Genetics, National Human Genome Research Institute, NIH Building 10, 10 Center Drive, Bethesda, MD 20892, USA.
Arthritis Rheum. 2004 Nov;50(11):3698-701. Abstract quote  

Alkaptonuria, a rare autosomal-recessive disorder caused by mutations in the HGD gene and a deficiency of homogentisate 1,2-dioxygenase, is characterized by accumulation of homogentisic acid (HGA), ochronosis, and destruction of connective tissue resulting in joint disease. Certain medications have been reported to cause cutaneous hyperpigmentation resembling that of alkaptonuria.

We present 5 such cases. Eighty-eight patients with a possible diagnosis of alkaptonuria were examined at the National Institutes of Health Clinical Center between June 2000 and March 2004. The diagnosis of alkaptonuria was confirmed or ruled out by measurement of HGA in the urine. Five patients with findings consistent with ochronosis, including pigmentary changes of the ear and mild degenerative disease of the spine and large joints, were diagnosed clinically as having alkaptonuria, but the diagnosis was withdrawn based on normal urine HGA levels. All 5 patients were women who had taken minocycline for dermatologic or rheumatologic disorders for extended periods.

Minocycline-induced hyperpigmentation should be considered in the differential diagnosis of ochronosis. This could be of increased significance now that minocycline and other tetracyclines have been proposed as therapeutic options for rheumatoid arthritis, bringing a new population of patients with ochronosis and arthritis to medical attention with the potential, but incorrect, diagnosis of alkaptonuria.

 

PROGNOSIS CHARACTERIZATION

 

TREATMENT CHARACTERIZATION
GENERAL  
New developments in ochronosis: review of the literature.

Keller JM, Macaulay W, Nercessian OA, Jaffe IA.

Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY, USA.


Rheumatol Int. 2005 Mar;25(2):81-5. Epub 2004 Aug 21. Abstract quote  

Ochronosis commonly affects all connective tissue. Recognition of changes secondary to the deposition of ochronotic pigments has increased with advances in diagnostic technology, allowing both improved imaging and early biochemical and genetics-based diagnosis of alkaptonuria, the cause of ochronosis.

Successful symptomatic treatment of ochronotic arthropathy with joint replacement has been documented, and a new pharmacotherapeutic agent, nitisinone, is currently under investigation for both prevention and treatment of ochronosis.

This review of the literature highlights recently recognized complications, new diagnostic techniques, and treatment options.
LASER-SKIN  
Treatment of exogenous ochronosis with a Q-switched alexandrite (755 nm) laser.

Bellew SG, Alster TS.

New Jersey Medical School, Newark, New Jersey, USA.

Dermatol Surg. 2004 Apr;30(4 Pt 1):555-8. Abstract quote  

BACKGROUND: Exogenous ochronosis is a cutaneous disorder characterized by blue-black or slate-gray hyperpigmentation resulting from the prolonged use of certain topical agents, most commonly hydroquinones. It is notoriously difficult to treat.

OBJECTIVE: To report the effectiveness of a quality-switched (QS) 755-nm alexandrite laser in treating hydroquinone-induced exogenous ochronosis.

METHODS: Hydroquinone-induced exogenous ochronosis in two patients was treated with a QS alexandrite laser. The first patient received six treatments (average fluence=7.8 J/cm(2)) at 2-month intervals. The second patient received four treatments (average fluence=6.9 J/cm(2)) at 4-month intervals. Biopsies of lesional skin were obtained before and after laser treatment for histologic evaluation.

RESULTS: Significant lightening of the pigmented skin areas was achieved in both patients without scarring or textural changes. Decreased dermal pigmentation was observed on histologic examination of treated skin specimens.

CONCLUSION: The QS alexandrite laser can effectively treat exogenous ochronosis without untoward side effects.
NITISINONE  
Use of nitisinone in patients with alkaptonuria.

Suwannarat P, O'Brien K, Perry MB, Sebring N, Bernardini I, Kaiser-Kupfer MI, Rubin BI, Tsilou E, Gerber LH, Gahl WA.

Section on Human Biochemical Genetics, Medical Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892-1852, USA.

Metabolism. 2005 Jun;54(6):719-28. Abstract quote  

Alkaptonuria, a rare autosomal recessive disorder caused by mutations in the HGD gene and deficiency of homogentisate 1,2 dioxygenase, is characterized by ochronosis, arthritis, and daily excretion of gram quantities of homogentisic acid (HGA). Nitisinone, an inhibitor of the enzyme 4-hydroxyphenylpyruvate dioxygenase, can drastically reduce urinary excretion of HGA in individuals with alkaptonuria.

We investigated the safety and the HGA-depleting efficacy of nitisinone in an open-label, single-center study of 9 alkaptonuria patients (5 women, 4 men; 35-69 years of age) over the course of 3 to 4 months. Each patient received nitisinone in incremental doses, 0.35 mg bid followed by 1.05 mg bid, and remained on this dosage and a regular diet for 3 months. Nitisinone reduced urinary HGA levels from an average of 4.0 +/- 1.8 (SD) g/day to 0.2 +/- 0.2 g/day ( P < .001). The average plasma tyrosine concentration, initially 68 +/- 18 mmicro mol/L, rose to 760 +/- 181 micro mol/L ( P < .001). During the final week of the study, 5 patients adhered to a protein-restricted diet (40 g/day), and their mean plasma tyrosine level fell from 755 +/- 167 to 603 +/- 114 mu mol/L. Six of the 7 patients who received nitisinone for more than 1 week reported decreased pain in their affected joints. Weekly ophthalmologic examinations showed no signs of corneal toxicity. Adverse events included the passing of kidney stones, the recognition of symptoms related to aortic stenosis, and elevation of liver transaminase levels.
 
We conclude that low-dose nitisinone effectively reduced urinary HGA levels in patients with alkaptonuria. Future long-term clinical trials are planned to determine the benefits of nitisinone in preventing joint deterioration and providing pain relief, and its long-term side effects.
SURGERY  
Hip arthroplasty for ochronosis.

Kerimoglu S, Onder C, Aynaci O, Malkoc CH.

Department of Orthopedic Surgery, Karadeniz Technical University Faculty of Medicine, Trabzon 61080, Turkey.
Saudi Med J. 2005 Nov;26(11):1812-4. Abstract quote  

Alkaptonuria is a metabolic disorder in which homogentisic acid oxidase is absent. Therefore, homogentisic acid accumulates in cartilage and connective tissues.

We can diagnose ochronotic arthropathy, a manifestation of long standing alkaptonuria, through careful radiological, physical, and laboratory examination. In this report, we describe 4 cases of ochronotic arthropathy to which we applied cementless total hip prosthesis due to severe hip involvement.
Arthroscopic treatment of shoulder ochronotic arthropathy: a case report and review of literature.

Castagna A, Giombini A, Vinanti G, Massazza G, Pigozzi F.

Humanitas Clinical Institute, Rozzano, Milan, Italy.

Knee Surg Sports Traumatol Arthrosc. 2006 Feb;14(2):176-81. Epub 2005 Aug 3. Abstract quote  

Alcaptonuria is an inherited hereditary metabolic disorder, which is associated with various systemic abnormalities and related to the accumulation of homogentisic acid and a derived melanine-like pigment in the connective tissues; the latter is termed ochronosis.

We present the arthroscopic findings in the shoulder of a 58-year-old female with ochronotic arthropathy and discuss the role of arthroscopy in the diagnosis and management of this rare metabolic disorder.

Arthroplasty for ochronotic arthritis: no failure of 11 replacements in 3 patients followed 6-12 years.

Spencer JM, Gibbons CL, Sharp RJ, Carr AJ, Athanasou NA.

Nuffield Department of Orthopaedic Surgery, University of Oxford, Nuffield Orthopaedic Centre, Headington, Oxford OX3 8JU, UK.
Acta Orthop Scand. 2004 Jun;75(3):355-8. Abstract quote  

BACKGROUND: Alkaptonuria is a rare single-gene disorder characterized by black pigmentation of cartilage and other connective tissues. Premature degenerative arthritis affects the large joints in many of these of patients. Medical treatment is limited to a protein-restricted diet (phenylalanine and tyrosine) with surgery reserved for end-stage joint disease. As in other metabolic bone diseases, there are concerns about the quality and strength of affected bones and therefore the suitability and longevity of replacement arthroplasty. The histopathology and outcome of joint replacement for alkaptonuric arthritis is unknown and limited to sporadic case reports.

PATIENTS AND RESULTS: We describe 11 joint replacements in 3 patients with alkaptonuric polyarthropathy, including shoulder and elbow replacements not previously reported. No prosthetic failures occurred in up to 12 years of follow-up.

INTERPRETATION: Total joint replacement is an acceptable treatment for degenerative joint disease in alkaptonuric patients, with implant survival comparable to that found in patients with osteoarthritis.

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