Ochronosis

Etiology

Inherited in an autosomal recessive fashion, alkaptonuria is an inactive gene mapped on chromosome 3q21-23 coding for the enzyme homogentisate 1,2 dioxygenase, also known as HGD. This enzyme is critical as a component of phenylalanine/tyrosine catabolism, a principal degradation pathway for these amino acids.[4]

The result is systemic sequestration of homogentisate – a colorless phenol that - upon the decay to benzoquinone, can irreversibly bind with collagen. Another effect is that polymerization of this molecule takes on an iridescent dark hue, tinting affected tissue and also known for turning urine black. Aside from just discoloration, these processes can cause degradation, degeneration, and developmental problems in all types of collagen.[1]

Exogenous ochronosis is a limited cutaneous version of the same process. In exogenous ochronosis, various phenolic compounds enzymatically inhibit homogentisate dioxygenase. The result is chemically very similar to alkaptonuria, albeit localized to the skin. Common phenols responsible for exogenous ochronosis are quinines/antimalarials, [5]resorcinol/acne medications, picric acid, and the increasingly infamous hydroquinone, a potent melanin inhibitor utilized in cosmetics as well as medication.[6]

Epidemiology

The prevalence of alkaptonuria and endogenous ochronosis in most ethnic groups is less than 1 in 100,000. Only 22 cases have been definitively diagnosed in the United States for the past five decades. It is a rare disease, in specific populations, it can be orders of magnitude more common (e.g., the Dominican Republic and Slovakia with a known prevalence of 1 in 20,000).

The prevalence of exogenous (acquired) ochronosis appears to be significantly more widespread in sub-Saharan Africa, where culprit phenols such as antimalarials and depigmentation agents are utilized in higher frequencies, concentration, and duration.[3]

Pathophysiology

The mutations responsible generally appear on exons of 6, 8, 10, and 13 of the HGD gene coding for the enzyme homogentisate dioxygenase. However, over 100 abnormalities are recorded and even a rare autosomal dominant variant that has yet to be genetically characterized.[4]

Homogentisate dioxygenase, a hexamer metalloprotein, is chiefly responsible for converting homogentisate into maleyacetoacetate, and eventually ketones for excretion. When defective an obvious sequester of the substrate, homogentisate increases by 2 to 3 orders of magnitude in the serum. Despite being renally-cleared, colorless, and water-soluble, it quickly degrades into benzoquinone acetate, which shares non of those attributes. Furthermore, benzoquinone precipitates and polymerizes into collagen.[7]

History and Physical

The earliest sign is from parents who notice that their infants’ soiled diapers are black in color. Skin and bone discoloration can be striking, or this disease can be insidious and manifest later in life.[1]

Patients may present with back pain or large joint arthralgias in their post-teenage years or early 30s. Pigmentation of the sclera and pinna of the ear, although classic, is often seen later in life. The severity can be extremely variable and holds little prognostic value.[8]

Constant tendon ruptures at multiple sites, especially with minimal trauma, is also a red flag. On physical exam, thickened Achilles tendon and bursa effusions are common for those with this condition.[8]

Aortic valve murmurs are heard at a much earlier point in life as well, often without predisposing congenital anomalies such as a bicuspid aortic valve.[9]

Evaluation

For alkaptonuria, a chromatography assay in the urine for homogentisate can be diagnostic, especially, if the color change is noted after being exposed to the air.[10]

A genetic test can determine the existence of the autosomal recessive disease in an individual and also those who are heterozygous carriers. Currently, these genomic databases are maintained by the genetic testing registry.

For exogenous ochronosis, a suspicion could be based on history, including past medications that are known phenols.

Ultraviolet photography can rule in/out known differentials, but because of the concomitance with melasma, its use has fallen, including both inducted fluorescence and time-lapse, or a just a simple a woods lamp observation.[11]

Skin biopsy with histological confirmation is the gold standard.

Confocal microscopy is emerging as a viable option for noninvasive diagnosis.[12]

Treatment / Management

Being important as a cofactor and even a partial substrate in several stages of tyrosine catabolism, collagen renewal, and development, ascorbate (vitamin C) has historically been tried via megadosing but without much success or efficacy.[13]

Tyrosine and phenylalanine dietary restrictions have been successful for phenylketonuria treatment though it is particularly hard to accomplish, and efficacy is similar to vitamin C megadosing.[13]

Nitisinone, approved as first-line treatment for the closely related disease, hereditary tyrosinemia, is the only intervention proven to modify disease progression. As such, it is the mainstay of treatment, although its use should be judicious and carefully watched.[7][10](B3)

In addition to corneal checks for iatrogenic dendritic keratopathy, the anterior chamber should be assessed for normal pressure and changing pigmentation that predisposes individuals to glaucoma.

Tracking liver function tests, along with serum tyrosine measurements, is advisable for serological workup.

Neuropsychiatric follow-up is recommended, as this was a significant sequela seen in hereditary tyrosinemia.[14]

This substance blocks activity of hydroxyphenylpyruvate dioxygenase, the very enzyme required to form homogentisate from hydroxyphenylpyruvate, its precursor. Nitisinone has shown much promise in normalizing homogentisate serum levels.

Historically, acquired or iatrogenic ochronosis was notoriously difficult to treat aside from skin grafting, with chemical peeling via glycolic acid and derma-abrasion.

With exogenous ochronosis, treatment was primarily preventative, and stopping the use of offending agents should still be a first-line approach, along with dietary tyrosine/phenylalanine reduction, but recent advancements in photobiomodulation and photodynamic therapy are new therapies.[3][6]

Differential Diagnosis

Alkaptonuria has a wide range of symptoms with equally wide differential to rule out. However, evaluating for seronegative arthropathies such as spondylosis is the primary approach. Alkaptonuria mimics symptoms closely with arthralgic pain in the large joints.

Sacroiliac sparing is especially concerning, but erosions, pseudo-widening of joint spaces, and sclerotic conversion of bone without articular cartilage involvement are key features to rule out the inflammatory arthropathies.[1]

Arthritis is clinically indistinguishable from osteoarthritis.

A full index of rheumatic blood parameters and observation of symptomatic response to NSAIDs (or DMARDs if started), should be noted as well.

Melasma is an important mimic for exogenous ochronosis, as the most commonly prescribed treatment (hydroquinone) will just worsen symptoms of exogenous ochronosis. Do note that these diseases often overlap, and iatrogenic paradoxical darkening from the overtreatment of melasma is a particular concern. The literature has not settled on the best management for these patients is not settled in the literature.[10][12]

Other differentials that cause discoloration of the skin should also be considerations. Argyria or chrysiasis from colloidal silver and gold salts respectively can tint the skin a bluish-grey as well.[6]

Prognosis

Life expectancy is close to normal for alkaptonuria, but the effect on the quality of life merits attention.

Early in life, most afflicted patients are asymptomatic except for the staining of their clothes. It is advisable to follow the phenol deposition with serial DEXA scans and asses growth, which can become stunted, and nutrition requires assessment for limiting those that are phenylalanine/tyrosine dense.

Arthralgia and arthritis are almost universal in affected patients, and they could expect joint replacement from ochronotic arthritis from as young as age 30.[1] The cartilage involvement, in particular, accelerates the bone on bone symptoms seen from osteoarthritis.[8] The involvement of the thoracic and lumbar spine, especially the intervertebral discs, leads to debilitating back pain.

More prognostically concerning as a corollary of ochronosis is the involvement of the valvular leaflets in the heart. Ochronosis tends to affect the aortic valve the most, and aortic insufficiency is often a culprit in early heart disease.[1][9]

Finally, patients have an increased incidence of both kidney and prostatic stone formation.[1]

Complications

Those treated with the herbicide nitisinone require close monitoring with long term use, particularly symptoms of dendritic keratopathy as an asymptomatic and insidious complication.[14]

Kidney function stays normal despite the filtration of large amounts of homogentisate; any reductions in creatinine clearance is from likely from other comorbidities.