Are You Confident of the Diagnosis?
What you should be alert for in the history
Alkaptonuria (AKU) is a rare autosomal recessive disease of tyrosine metabolism that is caused by a deficiency of the enzyme homogentisic acid oxidase (HGAO). Ochronosis is almost a synonym, but technically describes dark pigment deposits on connective tissue, no matter what the cause.
Endogenous ochronosis develops as the result of alkaptonuria connective tissue involvement, and arises in approximately 50% of alkaptonuric patients. Exogenous ochronosis presents as an acquired asymptomatic hyperpigmentation on photoexposed areas, predominantly over bony prominences, and is caused by the topical application of several skin-lightening agents, especially hydroquinones.
Characteristic findings on physical examination
Findings include darkening of the urine, the symptom that gives the name “alkaptonuria” to this disease. Dark urine is the diagnostic finding in only 50% of cases, either because freshly voided urine is normal in color, or because individuals do not notice this discoloration. Clinical symptoms, aside from dark-stained diapers, are generally present only after the third decade of life.
Alkaptonuric patients should be asked about a history of connective tissue involvement such as pigmentation of ear cartilage and skin pigmentation, or early-onset arthritis. Patients should also be asked about changes of color in clothing (especially in areas of sweating) and the appearance of bluish-black pigmentation over the cheeks, nose, ears, eyes, apposing surfaces of the thumb and index finger, and knuckle pads. Patients may also report back pain, crippling, or stiffness.
Examine the external ears in patients with unexplained arthritis.
Be alert for topical or systemic medications patients are using to exclude exogenous ochronosis.
There are three major features of alkaptonuria:
HOMOGENTISIC ACID (HGA) IN THE URINE
Oxidation of the HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark after standing (Figure 1). Individuals with alkaptonuria usually have dark urine or urine that turns dark on standing or exposure to an alkaline agent; however, darkening may not occur for several hours after voiding and many patients never observe any abnormal color to their urine. , Diaper discoloration could be the first sign of the disease (50%).
OCHRONOSIS (BLUISH-BLACK PIGMENTATION OF CONNECTIVE TISSUE)
Accumulation of HGA and its oxidation products (e.g., benzoquinone acetic acid) in connective tissue leads to ochronosis.
Brown pigmentation of the sclera is observed midway between the cornea and the outer and inner canthi at the insertion of the recti muscles (Osler’s sign) (see Figure 2). Pigment deposition may also be seen in the conjunctiva and cornea. The pigmentation does not affect vision.
Ear cartilage pigmentation is first seen in the concha and antihelix, and later in the tragus. The cartilage is slate blue or gray and feels irregular or thickened (see Figure 3). Calcification of the ear cartilage may be observed on radiographs.
Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. The sweat glands are rich in ochronotic pigment granules, and intradermal injection of epinephrine into the skin of the axillary vault will yield brown-black sweat droplets in the follicular orifices (see Figure 4).
A deep purple discoloration may be seen on the skin of the hands, corresponding to the underlying tendons, or in the web between the thumb and the index finger (see Figure 5). Extensive or rapidly progressive skin pigmentation has been reported with impaired renal status, presumably due to decreased renal clearance of HGA. The discoloration tends to be most pronounced in sun-exposed sites; in areas of high eccrine gland density such as the axillae, palms, and soles; on the genitals; and in cartilage, especially of the ear and nose.
By the age of 55 , 50% of patients have undergone at least one joint replacement. Arthritis often begins in the spine and resembles ankylosing spondylitis in its large-joint distribution. Spondylopathy precedes peripheral arthropathy. Spinal involvement is first noted in the lumbar and later in the thoracic spine. Radiographs of the spine showing flattened and calcified intervertebral disks are pathognomonic.
Findings include degeneration of the intervertebral disks, followed by disk calcification and eventually fusion of the vertebral bodies. Osteophyte formation and calcification of the intervertebral ligaments are minimal. Radiographs of the large joints may show joint space narrowing, subchondral cysts, and infrequent osteophyte formation. Enthesopathy can be seen at the muscle insertions.
Individuals with exogenous ochronosis are referred with focal darkening of the skin, most commonly seen after hydroquinone application to lighten the skin. Three clinical stages have been identified in exogenous ochronosis:
1. Erythema and mild macular pigmentation
2. Darker pigmentation associated with dark caviar-like papules
The diagnosis of endogenous ochronosis is based on personal and family history, urine testing, and histology.
Expected results of diagnostic studies
Urine tests include qualitative assays for HGA. The presence of HGA can be confirmed with gas chromatography and mass spectrophotometry. The amount of HGA excreted per day in individuals with alkaptonuria is often 1-8g. A normal 24-hour urine sample contains 20-30mg of HGA.
Freshly voided urine is usually of normal color, but urine left standing turns brownish-black due to the gradual oxidation of HGA. The oxidation can be accelarated by alkalinization with sodium hydroxide. Alkalinized affected urine turns unexposed photographic paper black because silver salts on the paper are reduced to silver nitrite by HGA, giving rise to a black precipitate (Fishberg test). A yellow-orange precipitate caused by the reduction of copper forms when urine containing HGA is tested with Benedict’s reagent; the color of the supernatant solution is brownish-black, which indicates the diagnosis of alkaptonuria.
Routine histopathology of affected skin demonstrates ochre or yellow-brown pigment within the dermis. The pigment is seen within irregularly shaped degenerated, homogenized, and swollen collagen fibers that may display sharp jagged borders, and within macrophages, free within the dermis, in endothelial cells, and in the basement membrane and the secretory cells of eccrine glands.
Foreign body giant cells may be seen around the granules. Biopsy of the ear cartilage reveals condrocyte nuclear pyknosis, cartilage degeneration, and diffuse pigmentation. The pigment stains black with methylene blue or cresyl violet. Electron microscopic examination of the ochronotic pigment reveals homogenous electron-dense material with loss of collagen fibril periodicity (see Figure 6).
Exogenous ochronosis shows similar histologic findings early in its course. In later stages of the disease, the ochronotic collagen fibers degenerate into amorphous eosinophilic material, and a granulomatous and lichenoid infiltrate may occur. Antimalarial pigmentation contains increased melanin and hemosiderin in addition to ochronotic pigment.
If required; molecular genetic testing is available on a clinical basis.
The differential diagnosis of endogenous ochronosis includes: porphyria, hemoglobinuria, hyperbilirubinuria, myoglobinuria, and melanuria. Ocular ochronosis could be mistaken for melanoma.
Localized cutaneous pigmentation can occur with the use of minocycline and other tetracyclines, phenothiazines, or heavy metals. Patients with alkaptonuria have been misdiagnosed with acute intermittent porphyria. Localized argyria can resemble ochronosis clinically and histologically.
The differential diagnosis of ochronotic arthropathy includes ankylosing spondylitis, calcium pyrophosphate dihydrate deposition, herniated disc, and idiopathic atrophic osteoarthritis. Radiographic findings of the spine differentiate AKU from rheumatoid arthritis and osteoarthritis. Ochronotic arthritis does not affect small joints of the hands and feet as in rheumatoid arthritis. Alkaptonuria spares the sacroiliac joints and syndesmophytes; an annular ossification with a bamboo pattern does not occur, in contrast to ankylosing spondylitis (AS). In addition, the HLA-B27 antigen is highly positive in AS.
A detailed history (medication, family, and personal), combined with failure to demonstrate the excretion of HGA in the urine, should eliminate false positive diagnoses.
The main differential diagnosis of exogenous ochronosis is melasma. Exogenous ochronosis is more resistant to treatments.
Who is at Risk for Developing this Disease?
Alkaptonuria is a very uncommon disorder, with an incidence of 1:300,000-1,000,000. It is most common in the Dominican Republic and Slovakia (estimated rate is 1:25,000).
Ask the patient about a family history; however, a family pedigree usually reveals no other affected individuals because alkaptonuria is autosomal recessive. Many patients are asymptomatic; therefore, the low frequency of affected family members may be due to a lack of ascertainment.
In general, the severity of the disease progresses after the age of 30 and develops more rapidly in men than in women.
Exogenous ochronosis typically occurs in dark-skinned patients who use high-strength skin lightening agents such as hydroquinones; however, low concentrations may result in this paradoxical darkening of the skin. Generally, bleaching creams must be used at least 6 months, demonstrating hyperpigmentation that is usually limited to the exposed area. Phenol, resorcinol, antimalarials, tetracyclines, phenothiazine, amiodarone, heavy metals, and chemotherapeutic agents could be the responsible agents. Ochronosis has also been reported following quinine injections and prolonged use of carbolic dressings.
What is the Cause of the Disease?
Alkaptonuria is caused by deficiency of renal and hepatic homogentisate 1,2-dioxygenase, an enzyme that converts homogentisic acid (HGA) to malylacetoacetic acid in the phenylalanine and tyrosine degradation pathway. It is inherited in an autosomal recessive pattern. The human gene for alkaptonuria has recently mapped to chromosome 3q. Because of the enzymatic block, HGA is oxidized and polymerized by the enzyme polyphenol oxidase, present in skin and cartilage, to the active product benzoquinone acetic acid. This melanin-like product is believed to bind irreversibly to collagen.
There are several theories that attempt to explain the clinical manifestations of AKU. It seems that HGA inhibits several important enzymes such as lysyl hydroxylase for the cross-linking of collagen fibers; HGA and its oxidation products may also act as chemical irritants or physically bind to connective tissue, resulting in weakness, inflammation, and degeneration.
More than one pigment may be formed by the oxidation of HGA. These pigments (eumelanin and melanin) appear similar; however, eumelanin differs from melanin by being more resistant to bleaching with hydrogen peroxide.
Arthritis in patients with AKU is caused by chemical irritation of deposited HGA, an altered metabolism of chondrocytes, and altered cross linkage of collagen.
The cause of exogenous ochronosis is unclear. Local inhibition of HGAO by hydroquinone, followed by pigment polymerization, may be the cause. Another hypothesis involves increased tyrosinase activity by hydroquinone. Functional melanocytes are important in the pathogenesis of ochronosis. Sun exposure may activate melanocytes and explain the distribution of ochronosis as well. Common to both endogenous and exogenous ochronosis are phenolic intermediates that can be converted into melanin-like precursors.
Systemic Implications and Complications
The most clinically relevant organ systems involved in AKU are musculoskeletal, genitourinary, cardiovascular, eye, and skin.
Skeletal disease is an important source of morbidity and may lead to disability.
Urine darkening or diaper discoloration can be followed by the occurrence of soft black calculi, obstruction, and urinary tract infections. Although renal failure may infrequently occur in later stages of alkaptonuria, in most cases it is probably a consequence of the long use of nonsteroidal anti-inflammatory drugs used to treat the arthritis.
Cardiovascular system findings include pigment deposition of the mitral and aortic valves, secondary valvular dystrophic calcifications, murmurs, aortic stenosis, and bluish-black pigmentation of the endocardium, aortic intima, and coronary arteries.
Triangular-shaped areas of brownish pigmentation on the lateral and medial parts of sclera (Osler’s sign), and pigmentation of the corneas, conjunctivae, tarsal plates, and eyelids may occur.
Pigmentation of the cerumen, the tympanic membranes, and the ossicles may also occur, which may lead to tinnitus or deafness.
Heavy deposition of HGA may occur in laryngeal, tracheal, and bronchial cartilage and may cause hoarseness and dysphagia.
Exogenous ochronosis has no systemic implications.
Treatment options for endogenous ochronosis are summarized in Table I.
|Ascorbic acid||Protein-restricted diet||Replacement therapy (recombinant enzyme)|
Treatment options for exogenous ochronosis are summarized in Table II.
|Medical Treatment||Surgical Treatment|
|Topical retinoic acid 0.05%||Dermabrasion|
|Kojik acid||Carbon dioxide laser/ Q-switched alexandrite (755nm) laser|
|Sunscreens with a high sun protection factor|
Optimal Therapeutic Approach for this Disease
Inform the patient about the natural history and morbidities of the illness. There is no definitive cure for endogenous ochronosis, and treatment is aimed by controlling and ameliorating symptoms.
Alkaptonuria-associated arthritis is usually treated with nonsteroidal anti-inflammatory drugs and appropriate physiotherapy.
Pharmacotherapeutic approaches and dietary manipulations are generally unsuccessful, and symptomatic treatment should be preferred.
Encourage the patient to adopt a protein-restricted diet (1.3g/kg/day dietary restriction of tyrosine and phenylalanine). Try ascorbic acid, as it is safe and its antioxidant properties may eventually retard the conversion of HGA to polymeric material, but clinical efficacy is not confirmed. Large doses of vitamin C (1g/day) could be used to prevent the deposition of ochronotic pigment.
Other antioxidants such as N-acetyl cystein and Vitamin E can be added to medical therapy; they have been shown to reduce HGA polymerization and in vitro accumulation.
Use of nitisinone, an inhibitor of the enzyme that forms HGA (i.e., para-hydroxyphenylpyruvic acid dioxygenase), lowers HGA production. Nitisinone has also been shown to reduce urinary excretion of HGA. The dosage in adults is 0.35mg per oral, twice a day.
As the gene responsible for alkaptonuria has been identified, replacement therapy with recombinant enzyme could be a new approach in the treatment of the disease. Genetic counseling should be offered.
Treatment of exogenous ochronosis requires that the patient stop using the responsible agent immediately. Retinoic acid plus sunscreens, dermabrasion, or carbon dioxide laser can be tried, but treatment has varying degrees of success.
Explain the natural history of the disease to the patient: Alkaptonuria does not appear to reduce the lifespan of affected subjects, but there is a high rate of disability, especially late in life.
Encourage the patient to have regular follow-up visits with orthopedics, cardiology, urology, ophthalmology, and physical therapy, and rehabilitation, in addition to dermatology.
Perform echocardiography on patients over age 40 to detect cardiovascular involvement.
Explain the circumstances to avoid. Physical stress to the spine and large joints, including heavy manual labor or high impact sports,can increase the progression of severe arthritis.
Emphasize the testing of relatives at risk.
Call patients every 6 months to monitor treatment efficacy and detect adverse effects of the medication.
Patients treated with dietary phenylalanine and tyrosine restrictions must be biochemically monitored.
For patients prescribed nitisinone, monitor hepatic function using imaging and laboratory tests, perform a hemogram to detect thrombocytopenia and leukopenia, and consult an ophhalmologist to predict corneal toxicity.
Unusual Clinical Scenarios to Consider in Patient Management
In rare cases, isolated skin plaques can appear as the leading symptom, and can be misdiagnosed. Generalized skin pigmentation is not usually observed unless there is renal dysfunction.
Chronic back pain in young individuals with typical bluish-black pigmentation in the ears should suggest the diagnosis.
When a patient being treated for an ongoing arthritis has a negative serology and a history of nephrolithiasis, suspect the diagnosis of AKU.
Rheumatoid factor (RF), HLA-B27, and a detailed urinary inspection can be useful.
Dermatologists should consider the diagnosis of exogenous ochronosis in refractory cases of melasma.
What is the Evidence?
Turgay, E, Canat, D, Gurel, MS, Yuksel, T, Baran, MF, Demirkesen, C. “Endogenous ochronosis”. Clin Exp Dermatol . vol. 34. 2009. pp. 865-8. (The dramatic case report provides photographic documentation of this entity)
Peker, E, Yonden, Z, Sogut, S. “From darkening urine to early diagnosis of alkaptonuria”. Indian J Dermatol Venereol Leprol . vol. 74. 2008. pp. 700(This article presents a good description of early diagnosis in alkaptonuria.)
Turiansky, GW, Levin, SW. “Bluish patches on the ears and axillae with dark urine: ochronosis and alkaptonuria”. Int J Dermatol. vol. 40. 2001. pp. 333-5. (This article helps us understand the important role of the dermatologist in diagnosing this metabolic disease.)
Diaz-Ramon, JL, Aseguinolaza, B, Gonzales-Hermosa, MR, Gonzales-Perez, R, Caton, B, Soloeta, R. “Endogenous ochronosis: a case description”. Actas Dermosifiliogr . vol. 96. 2005. pp. 525-8. (This is a valuable discussion about the major clinical features of the disease.)
Phornphutkul, C, Introne, WJ, Perry, MB, Bernardini, I, Murphey, MD, Fitzpatrick, DL. “Natural history of alkaptonuria”. N Engl J Med . vol. 347. 2002. pp. 2111-21. (This is an excellent article describing the natural history of the disease.)
Ribas, J, Schettini, AP, Cavalcante Mde, S. “Exogenous ochronosis hydroquinone induced: a report of four cases”. An Bras Dermatol . vol. 85. 2010. pp. 699-703. (The latest article, with rich content about exogenous ochronosis.)
Mannoni, A, Selvi, E, Lorenzini, S, Giorgi, M, Airo, P, Cammelli, D. “Alkaptonuria, ochronosis and ochronotic arthropathy”. Semin Arthritis Rheum . vol. 33. 2004. pp. 239-48. (This article describes the typical and atypical facets of alkaptonuria and ochronosis.)
Fisher, AA, Davis, MW. “Alkaptonuric ochronosis with aortic valve and joint replacements and femoral fracture: a case report and literature review”. Clin Med Res . vol. 2. 2004. pp. 209-15. (This is an excellent discussion, with a large bibliography.)
Suwannarat, P, O’Brien, K, Perry, MB, Sebring, N, Bernardini, I, Kaiser-Kupfer, MI. “Use of nitisinone in patients with alkaptonuria”. Metabolism . vol. 54. 2005. pp. 719-28. (This article provides very current knowledge about the usage of nitisinone and it is an extraordinary study in this area.)
de Haas, V, Carbasius Weber, EC, de Klerk, JB, Bakker, HD, Smit, GP, Huijbers, WA. “The success of dietary protein restriction in alkaptonuria patients is age-dependent”. J Inherit Metab Dis . vol. 21. 1998. pp. 791-8. (This article illuminates the long-term beneficial effects of the diets used in the treatment of alkaptonuria.)
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