History & Epidemiology

Derived from the Greek word “ochre,” meaning pale yellow, ochronosis is a rare disease characterized by a blue-black or gray-blue pigmentation. It is caused by deposits of yellow or ochre-colored pigment and typically affects the skin, the cartilage of the ears, and eye sclerae. Ochronosis tends to occur in adults, but it has also been observed in infants and children.

Ochronosis may be either endogenous (alkaptonuric) or exogenous.¹

The prevalence of endogenous ochronosis in most ethnic groups is less than 1 in 100,000. There have only been 22 cases definitively diagnosed in the United States in the past 50 years. Rates of alkaptonuric ochronosis are higher in the Dominican Republic and Slovakia.

Exogenous ochronosis is more widespread in sub-Saharan Africa, where certain types of medication, including antimalarials and depigmentation agents, are used more often, for longer times, and at higher doses.²

Alkaptonuric Ochronosis

Inherited in an autosomal recessive pattern, alkaptonuric ochronosis is thought to be caused by a mutation in the homogentisate 1,2-dioxygenase (HGD) gene, which results in the buildup of homogentisic acid (HGA) in cartilage, causing affected tissue to grow weak and brittle with time. This sets the stage for chronic inflammation, joint pain, and osteoarthritis. Most affected are bones and cartilage of the lower back, knees, shoulders and hips. It also stimulates melanin production and leads to increased urinary excretion of HGA.²

Exogenous Ochronosis

Several medications, including anti-malarial drugs and skin-lightening creams, have been reported to cause exogenous ochronosis along with over-exposure to the sun. Unlike alkaptonuric ochronosis, exogenous ochronosis is localized to skin.³

Ochronosis Diagnosis & Presentation

Parents may report that their infants’ soiled diapers are black. Early in life, most people with alkaptonuric ochronosis are asymptomatic, save for the staining of their clothes from sweat. Some patients may present with back pain or large-joint arthralgias in their 20s or early 30s. Later in life, pigmentation of the sclera and pinna of the ear may occur.

Alkaptonuric ochronosis symptoms on presentation may include:

Blue-black speckled discoloration in skin, sclera, ears, and nose
Reddish-brown or jet-black ear wax
Joint pain from the buildup of certain substances in the joints
Brown nails

The alkaptonuric ochronosis symptom trajectory generally starts with lower back pain and stiffness that can be debilitating. This is often followed by knee, shoulder, and hip pain over the subsequent decade. When cartilage becomes brittle and breaks apart, it can lead to spinal injuries, including prolapsed intervertebral discs. If deposits build up around the trachea, larynx, or bronchi, the patient may feel short of breath and have difficulty breathing. There’s also an increased risk of cardiac disease because deposits within the blood vessel walls can calcify.

Of note, pigmentation changes of the sclera do not affect vision. On exam, the sclera may have brown or gray deposits.

Other warning signs are frequent tendon ruptures in multiple locations, especially when there is little or no trauma, and aortic valve murmurs earlier in life without predisposing birth defects.

The severity of the pigmentation issues seen with alkaptonuric ochronosis does not confer any prognostic value.³

Exogenous ochronosis affects only the skin.²

Diagnostic Workup

The gold standard for diagnosis of alkaptonuric ochronosis is a skin biopsy with histological confirmation; however, confocal microscopy is emerging as an option.

Blood and urine tests can check for alkaptonuric ochronosis. Specifically, a chromatography assay in the urine for homogenization can be diagnostic. Gene testing can help identify autosomal recessive disease in an individual and heterozygous carriers.²

Upon physical exam, there may be thickened Achilles tendon and bursa effusions. Listen for aortic valve murmurs during the physical exam.²

Inquiring about past medications is key to diagnosing exogenous ochronosis. Other than the pigmentation changes, there are no symptoms of alkaptonuric ochronosis seen with this form of the disease.³

Drugs linked to exogenous ochronosis include:

Anti-malarial drugs such as quinacrine and quinine
Skin-lightening creams such as topical hydroquinone cream in high concentrations
Deposits of phenol or carboxylic acid³

Differential Diagnosis

Differential diagnoses include:

Argyria
Chrysiasis from colloidal silver and gold salts
Seronegative arthropathies, such as spondylosis
Melasma. This may be mistaken as exogenous ochronosis. Unfortunately, the most common treatment (hydroquinone) will only worsen symptoms.²

Management (Nonpharmacotherapy and Pharmacotherapy)

At present, there are no treatments specifically approved for alkaptonuric ochronosis. Reducing protein consumption may help those patients who receive their diagnosis early. Low protein diets have less of the amino acids phenylalanine and tyrosine, which produce homogentisic acid when metabolized.³

Consider a referral to a specialist to manage potential complications, such as joint or heart disease.²

Nitisinone is approved for hereditary tyrosinemia, which is related to ochronosis and may have disease-modifying properties. It is important to track liver function tests, along with serum tyrosine measurements, when patients take this drug. In addition, neuropsychiatric follow-up is recommended.²

Nitisinone may cause elevated tyrosine that can lead to keratopathy. Certain elimination diets may help reduce nitisinone-induced tyrosinemia in mice; phenylalanine restriction alone has proved ineffective. In addition, protein restriction significantly reduced circulating tyrosine in patients with alkaptonuric ochronosis.⁴

Doses of up to 1 g per day of vitamin C in older children and adults can slow the conversion of homogentisic acid to the polymeric deposits in cartilage and bone.³

Exogenous cutaneous ochronosis is treated by stopping the causative medication. There have been cases in which it has been successfully treated with lasers. In the future, photobiomodulation and photodynamic therapy may be treatment options for exogenous cutaneous ochronosis.²

Monitoring Side Effects, Adverse Events, Drug-Drug Interactions

Patients should undergo serial DEXA scans to follow phenol deposition to assess growth, which can be stunted with alkaptonuric ochronosis. These patients may need joint replacement from ochronotic arthritis at or around age 30.

When cartilage is involved, it speeds up bone-on-bone symptoms of osteoarthritis.

Patients should be monitored for early signs of heart disease, and aortic insufficiency is often found to be responsible. Alkaptonuric ochronosis patients should be monitored for formation of both kidney and prostatic stone formation.²

References

Bhattar PA, et al. Exogenous Ochronosis. Indian J Dermatol. 2015; 60: 537–543. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4681189/
Ochronosis. Stat Pearls. Updated Aug. 1, 2022. Accessed Sept. 12, 2022. https://www.statpearls.com/ArticleLibrary/viewarticle/26110
Alkaptonuria and ochronosis. New Zealand Dermatological Society. Accessed Sept. 12, 2022. https://dermnetnz.org/topics/alkaptonuria-and-ochronosis
Hughes JH, et al. Dietary restriction of tyrosine and phenylalanine lowers tyrosinemia associated with nitisinone therapy of alkaptonuria. Inherit Metab Dis. 2020; 43:259-268. doi: 10.1002/jimd.12172. https://pubmed.ncbi.nlm.nih.gov/31503358/

Author Bio

Denise Mann, MS, is a veteran freelance health writer in New York. Her work has appeared on HealthDay, among other outlets. She was awarded the 2004 and 2011 journalistic Achievement Awards from the American Society for Aesthetic Plastic Surgery. She was also named the 2011 National Newsmaker of the Year by the Community Anti-Drug Coalitions of America. She has also been awarded the Arthritis Foundation’s Northeast Region Prize for Online Journalism, the Excellence in Women’s Health Research Journalism Award, the Gold Award for Best Service Journalism from the Magazine Association of the Southeast, a Bronze Award from The American Society of Healthcare Publication Editors, and an honorable mention in the International Osteoporosis Foundation Journalism Awards. She was part of the writing team awarded a 2008 Sigma Delta Chi award for her part in a WebMD series on autism. Mann has a graduate degree from the Medill School of Journalism at Northwestern University in Evanston, Ill.