Ochronosis is named for the reddish-brown hue of tissue termed "ochre-like" that was first described by a young physician named Archibald Garrod in the early-19th century. In what he called an "inborn error of metabolism," Archibald Garrod changed history when he coined that term for the obscure "black urine" disease, alkaptonuria. He proposed that ochronosis was due to deposition of a phenolic compound – "alkaptons" polymerizing into connective tissue - because the enzyme that could cleave it was absent and was inherited as a "chemical individuality." This was insightful work given that this preceded the conceptualization of genes.
The work of Dr. Garrod would build core foundations on how we understand biochemistry, genetics, and medicine today. Alkaptonuria is iconic for being the initial description of the prototypical autosomal recessive disease.
Today we know that expression of the homogentisate 1,2 dioxygenase becomes stunted because of mutations arising in the HGD gene, described as Dr. Garrod's "chemical individuality." Serum levels of homogentisic acid (Alkaptons) concomitantly rise and polymerize into tissue over time. The sequestration effect is also termed as endogenous ochronosis.
This article reviews this and the exogenous form of ochronosis, commonly seen as a side-effect of medications that competitively inhibit the same enzyme mentioned above. In contrast to endogenous ochronosis, the deposition is often limited to the skin.
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.
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.
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, resorcinol/acne medications, picric acid, and the increasingly infamous hydroquinone, a potent melanin inhibitor utilized in cosmetics as well as medication.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Skin biopsy with histological confirmation is the gold standard.
Confocal microscopy is emerging as a viable option for noninvasive diagnosis.
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.
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.
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.
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.
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.
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.
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.
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.
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. The cartilage involvement, in particular, accelerates the bone on bone symptoms seen from osteoarthritis. 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.
Finally, patients have an increased incidence of both kidney and prostatic stone formation.
Those treated with the herbicide nitisinone require close monitoring with long term use, particularly symptoms of dendritic keratopathy as an asymptomatic and insidious complication.
Kidney function stays normal despite the filtration of large amounts of homogentisate; any reductions in creatinine clearance is from likely from other comorbidities.
Gene mapping can be beneficial for hopeful couples. It can help establish if both parents are heterozygous carriers of affected HGA genes.
For the more common exogenous ochronosis, deterrence center on socioracial issues, especially for women. For many cultures who are not of the White race, paler skin tones are seen as a desirable trait, leading some patients to over-medicate with high concentrations of depigmenting agents - often containing phenols such as hydroquinone and even NCAP (N-acetyl-4-s-cysteaminylphenol). The darker their complexion, hydroquinone's effects are the less pronounced and have a longer onset of action. Thus, these patients self-medicate with more frequent dosing and seek higher potency of medications. This cycle sadly leads to the paradoxical effects of ochronosis.
Addressing the afflicted patient's mental health, such as self-esteem and well-being, might be a venue of recourse, but the more significant societal-institutional issues involving classism, colorism, racism, etc. are well beyond the scope of this review, however.
Alkaptonuria is a rare metabolic disorder with interesting peculiarities. Frontline health providers should consider this diagnosis if parents are concerned for black stained diapers, or if the urinalysis sample darkens upon exposure to air. Unlike the closely associated phenylketonuria and hereditary tyrosinemias, alkaptonuria does not impair cognitive development and growth.
|||Phornphutkul C,Introne WJ,Perry MB,Bernardini I,Murphey MD,Fitzpatrick DL,Anderson PD,Huizing M,Anikster Y,Gerber LH,Gahl WA, Natural history of alkaptonuria. The New England journal of medicine. 2002 Dec 26 [PubMed PMID: 12501223]|
|||Zatkova A,Sedlackova T,Radvansky J,Polakova H,Nemethova M,Aquaron R,Dursun I,Usher JL,Kadasi L, Identification of 11 Novel Homogentisate 1,2 Dioxygenase Variants in Alkaptonuria Patients and Establishment of a Novel LOVD-Based HGD Mutation Database. JIMD reports. 2012 [PubMed PMID: 23430897]|
|||Bhattar PA,Zawar VP,Godse KV,Patil SP,Nadkarni NJ,Gautam MM, Exogenous Ochronosis. Indian journal of dermatology. 2015 Nov-Dec [PubMed PMID: 26677264]|
|||[PubMed PMID: 19862842]|
|||Tekgöz E,Akıncıoğlu E,Çınar M,Yılmaz S, A case of exogenous ochronosis associated with hydroxychloroquine. European journal of rheumatology. 2018 Sep [PubMed PMID: 30071940]|
|||Levin CY,Maibach H, Exogenous ochronosis. An update on clinical features, causative agents and treatment options. American journal of clinical dermatology. 2001 [PubMed PMID: 11705248]|
|||Taylor AM,Vercruysse KP, Analysis of Melanin-like Pigment Synthesized from Homogentisic Acid, with or without Tyrosine, and Its Implications in Alkaptonuria. JIMD reports. 2017 [PubMed PMID: 27943071]|
|||[PubMed PMID: 16981292]|
|||Shah A,Son A,Salehi P, Alkaptonuric ochronosis of the carotid artery. SAGE open medical case reports. 2020 [PubMed PMID: 32284865]|
|||Ranganath LR,Jarvis JC,Gallagher JA, Recent advances in management of alkaptonuria (invited review; best practice article). Journal of clinical pathology. 2013 May [PubMed PMID: 23486607]|
|||Fulton JE Jr, Utilizing the ultraviolet (UV detect) camera to enhance the appearance of photodamage and other skin conditions. Dermatologic surgery : official publication for American Society for Dermatologic Surgery [et al.]. 1997 Mar [PubMed PMID: 9145957]|
|||[PubMed PMID: 26988381]|
|||Judd S,Khedr M,Milan AM,Davison AS,Hughes AT,Needham A,Psarelli EE,Shenkin A,Ranganath LR, The nutritional status of people with alkaptonuria: An exploratory analysis suggests a protein/energy dilemma. JIMD reports. 2020 May [PubMed PMID: 32395409]|
|||Suwannarat P,O'Brien K,Perry MB,Sebring N,Bernardini I,Kaiser-Kupfer MI,Rubin BI,Tsilou E,Gerber LH,Gahl WA, Use of nitisinone in patients with alkaptonuria. Metabolism: clinical and experimental. 2005 Jun [PubMed PMID: 15931605]|
|||DeCaprio AP, The toxicology of hydroquinone--relevance to occupational and environmental exposure. Critical reviews in toxicology. 1999 May [PubMed PMID: 10379810]|