International Journal of Rheumatic Diseases 2014; 17: 327–332
ORIGINAL ARTICLE
Alkaptonuric ochronosis: a clinical study from Ardabil, Iran Ahad AZAMI, Nasrollah MALEKI and Zahra TAVOSI Department of Internal Medicine, Imam Khomeini Hospital, Ardabil University of Medical Sciences, Ardabil, Iran
Abstract Objective: Ochronosis is a term used to describe pigment deposition that occurs in the connective tissues of patients with alkaptonuria, an autosomal recessive disorder that results from a deficiency of homogentisic acid oxidase. Brown or blue-gray discoloration of the skin may be seen on the axillary and inguinal areas, face, palms or soles. In addition, blue-black discoloration can be apparent on skin overlying cartilage in which the pigment is deposited, such as the ears. The sclerae are also typically involved. The cheapest screening test to perform prior to expensive lab tests is the urine oxidation test: having it standing in light for a period of 24 h when suspicion has risen. Methods: Retrospective analysis of patients with ochronotic arthropathy seen between September 2011 to September 2013 was carried out. Results: Seven patients (four male, three female) with ochronotic arthropathy were seen, their mean age was 46.1 years. All patients had bluish-black pigmentations of the ear cartilage and sclera. Spondylosis was seen in all, whereas peripheral arthritis was present in five patients. Moderate aortic insufficiency and calcification of the aortic valve was detected in one male patient. Urine screening for homogentisic acid was positive in all seven patients. Conclusion: Alkaptonuria is a rare autosomal recessive disorder of the metabolism caused by deficiency of homogentisic acid oxidase. It is suggested that more widespread screening should be undertaken in order to assess the true incidence of the disorder. Key words: alkaptonuria, homogentisic acid, ochronosis, spondylosis.
INTRODUCTION Ochronosis is an autosomal recessive disorder that results from deficient activity of homogentisic acid dioxygenase (HGD), the third enzyme in tyrosine degradation.1 The description of alkaptonuria by Garrod in 1902 led to recognition of the concept of a single enzyme deficiency resulting in lifelong disease.2 The gene encoding HGD has been mapped to chromosome 3q21-q23 and mutations have been identified in patients with ochronosis.3 Affected patients usually are asymptomatic in childhood. During the third decade, Correspondence: Dr Nasrollah Maleki, Department of Internal Medicine, Imam Khomeini Hospital, Ardabil University of Medical Sciences, Ardabil, Iran. Email: [email protected]
deposits of the brownish or bluish pigment become apparent, typically first in the ear cartilage and sclerae. Additional pigment is deposited in the large joints and the spine, especially the lumbosacral region. Calcification of multiple intervertebral discs is a characteristic radiographic finding. Axillary and inguinal areas may have a brownish discoloration. Perspiration can stain clothing in affected patients.4 Ochronosis is characterized by the excretion of urine that appears normal when fresh, but turns dark brown or black if left standing or after alkalinization. The dark color is caused by oxidation of homogentisic acid (HGA), and alkaptonuria has also been called black urine disease. Cloth diapers that are washed in alkaline solutions will have dark brown staining. The diagnosis is confirmed by quantitative measurement of HGA in urine.5
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
A. Azami et al.
MATERIALS AND METHODS This study was a retrospective analysis of patients presenting with ochronotic arthopathy from September 2011 to September 2013. All patients with spinal stiffness, peripheral arthritis, limited joint mobility and pigmentation in connective tissues were screened for urinary homogentisic acid and if found positive were diagnosed to have ochronotic arthropathy. Complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum calcium, phosphorus, alkaline phosphatase, rheumatoid factor and human leukocyte antigen (HLA)-B27 examinations were performed. X-rays of knees, spines, pelvis and sacroiliac joints were taken. Cardiac and pulmonary evaluation included clinical examination, chest X-ray, high-resolution computed tomography (HRCT) of the lungs, electrocardiogram and echocardiogram. Joint swelling, tenderness and range of motion were assessed. Schober’s test, chest expansion, occiput to wall distance and finger to floor distance were measured. Screening was done for ochronosis at various sites such as the ear, eye and skin. Family history of alkaptonuria or ochronosis was recorded.
RESULTS
Figure 1 Bluish-black pigmentations of the ear cartilage and antihelix.
Figure 2 Dark pigmentation of the sclera in the interpalpabral fissures.
In the 3 years of the study period, seven patients (four male, three female) with ochronotic arthropathy were identified. Their average age was 46.1 years. Table 1 shows the demographic data of the patients. All patients had symptoms of low backache, spinal stiffness and inability to bend. On physical examination, all patients had bluish-black pigmentations of the ear cartilage and antihelix (Fig. 1), and dark pigmentation of the sclera on both eyes in the interpalpabral fissures (Fig. 2). Bluish-black discoloration on the lateral sides of the fingers was visible in six patients (Fig. 3) and dark
pigmentation of the nail beds was seen in one patient (Fig. 3). Inflammatory markers, calcium, phosphorus, alkaline phosphatase, rheumatoid factor and HLA-B27 were normal in all patients. The urine turned black on exposure to air for 6 h in all patients (Fig. 4). Peripheral arthritis occurred in five patients. Joints involved were knees in five patients, ankles in one and hip in two patients. Symptoms were pain, stiffness and limited mobility of the involved joints in all patients. On
Table 1 Demographic data of the patients Patients
Age (years)
Gender
Pigmentation of the sclera
Pigmentation of the ears
Pigmentation of the fingers
Peripheral arthritis
Spondylosis
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
43 49 48 45 64 32 42
Male Male Female Female Female Male Male
+ + + + + + +
+ + + + + + +
+
+ + + +
+ + + + + + +
328
+ + + + +
+
Cardiac involvement
+
International Journal of Rheumatic Diseases 2014; 17: 327–332
Alkaptonuric ochronosis
Figure 3 Bluish-black discoloration on the lateral side of the fingers and nail beds.
Figure 4 Urine turned black on exposure to air.
X-rays, sacroiliac joints were normal in all the patients, whereas dorso-lumbar spine showed loss of lordosis, osteophytes and wafer-like calcification of intervertebral discs in all patients (Fig. 5). Pulmonary evaluation was normal in all patients. Moderate aortic insufficiency and calcification of the aortic valve was detected in one male patient. Measurement of urinary organic acid levels showed a large quantity of homogentisic acid in all patients, which was consistent with a diagnosis of ochronosis. Treatment with nitisinone, vitamin C and dietary restrictions of food containing phenylalanine and tyrosine had proved to be successful in alleviating symptoms.
DISCUSSION Ochronosis is a rare autosomal recessive condition that is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts HGA to maleylacetoacetic
International Journal of Rheumatic Diseases 2014; 17: 327–332
acid in the tyrosine degradation pathway.6 This disease was first described by Garrod in 1902.2 The deficient enzyme was identified by La Du et al.7 in 1958. At least 1000 cases of ochronosis have been described; this is likely an underestimate.8 The incidence of this disease in the USA is 1 in 250 000 to 1 in 1 000 000 live births.9 Alkaptonuria occurs worldwide; a high prevalence has been observed in the Dominican Republic.10 The prevalence of alkaptonuria in Slovakia is estimated at 1 : 19 000.11 Alkaptonuria has three major features: 1) HGA in the urine. Oxidation of HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark upon standing. 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 individuals never observe any abnormal color to their urine. 2) 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. Pigment deposition may also be seen in the conjunctiva and cornea. The pigmentation does not affect vision.12 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. Calcification of the ear cartilage may be observed on radiographs. Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying
329
A. Azami et al.
Figure 5 X-rays showing loss of lordosis, osteophytes and wafer-like calcification of intervertebral discs.
tendons, or in the web between the thumb and index finger. 3) Arthritis. This often begins in the spine and resembles ankylosing spondylitis in its large-joint distribution. 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 wafer-like calcification of the intervertebral ligaments also occur. Radiographs of the large joints may show joint space narrowing, subchondral cysts and osteophyte formation. Enthesopathy can be seen at the muscle insertions.13 The presence of any of these features should prompt confirmatory biochemical testing. The cheapest screening test to perform prior to expensive lab tests is the urine oxidation test: having it standing in light for a period of 24 h when suspicion has risen. The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in the urine by gas chromatography-mass spectrometry analysis. The amount of HGA excreted per day in individuals with alkaptonuria is usually between 1–8 g.8 A normal 24-h urine sample contains 20–30 mg of HGA.14 The natural history of ochronosis was evaluated in a study of 58 patients, ages 4–80 years.9 Arthropathy was common, and one-half of the patients had replacement of one knee, hip or shoulder before 55 years of age.
330
Renal stones developed in 16 patients (27%), at a mean age of 64 years. The mean ages for detection of cardiac valve involvement and coronary artery calcification were 54 and 59 years, respectively. In the natural history study cited above, ochronosis was diagnosed before 1 year of age in 12 of 58 patients (21%). In the remaining patients, the mean age at diagnosis was 29 years. Levels of HGA are increased in blood, urine and tissue samples.9 Ochronosis resulting from alkaptonuria may be confused with acquired, reversible pigmentary changes following prolonged use of carbolic acid dressings for chronic cutaneous ulcers.8 Chemically induced ochronosis has also been described following long-term use of either the antimalarial agent Atabrineâ (quinacrine),15 the skin-lightening agent hydroquinone, or the antibiotic minocycline.16 In one case of alkaptonuria, the ochronotic pigment in the eye was misdiagnosed as melanosarcoma, resulting in enucleation of the eye.17 The arthritis of alkaptonuria resembles ankylosing spondylitis in its damage to the spine and large joints, although it differs in sparing the sacroiliac joint and in its radiographic appearance. Radiographic findings of the spine also differentiate alkaptonuria from rheumatoid arthritis and osteoarthritis. No effective therapy is available for ochronosis. Dietary restriction of tyrosine and phenylalanine will reduce the excretion of HGA, although the clinical effect is limited.18
International Journal of Rheumatic Diseases 2014; 17: 327–332
Alkaptonuric ochronosis
Joint pain is substantial in individuals with alkaptonuria, and close attention to pain control is necessary. Optimal pain management should be tailored to the individual with close follow-up and long-term management. Physical and occupational therapy are important to promote optimal muscle strength and flexibility. Knee, hip and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis.19 Pharmacologic treatment of alkaptonuria with oral administration of 2-(2-nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione (NTBC) or nitisinone has been proposed.20 Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone is approved for the treatment of tyrosinemia type I. Nitisinone reduced urinary HGA excretion by at least 69% in two individuals, but at the expense of an elevated plasma tyrosine concentration.9 The only known side effects are elevated plasma tyrosine concentration resulting in photophobia and, rarely, corneal crystals. In a pilot study, low-dose nitisinone reduced urinary HGA by up to 95% in nine individuals with alkaptonuria. In the same study, seven individuals were treated for up to 15 weeks with nitisinone while receiving normal protein intake; all had elevated plasma tyrosine concentrations. No ophthalmic, neurologic or severe dermatologic complications were observed. Two individuals had transient elevations in liver transaminase levels that returned to normal after stopping nitisinone.21 In a 3-year therapeutic trial, 2 mg of nitisinone daily reduced urine and plasma HGA by 95% throughout the study duration.14 Plasma tyrosine averaged 800 lmol/L without dietary restriction. Side effects were minimal. One affected individual developed corneal crystals that required discontinuation of nitisinone and one affected individual had elevated liver transaminases. High-dose vitamin C decreases urinary benzoquinone acetic acid, a derivative of HGA, but has no effect on HGA excretion.18 It has been hypothesized that highdose ascorbic acid may prevent the deposition of ochronotic pigment, although it does not alter the basic metabolic defect.18 No credible studies have demonstrated the clinical efficacy of ascorbic acid.8 Oral bisphosphonate therapy has been suggested to halt the progressive bone loss; however, a prospective
International Journal of Rheumatic Diseases 2014; 17: 327–332
study of four affected individuals failed to demonstrate benefit.22
CONCLUSION Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. This causes the classic clinical triad: (i) homogentisic aciduria; (ii) ochronosis; and (iii) arthritis, usually in the fourth decade of life. It is suggested that more widespread screening should be undertaken in order to assess the true incidence of the condition.
REFERENCES 1 La Du BN, Zannoni VG, Laster L, Seegmiller JE (1958) The nature of the defect in tyrosine metabolism in alcaptonuria. J Biol Chem 230, 251. 2 Garrod AE (1902) The incidence of alkaptonuria: a study in chemical individuality. Lancet 2, 1616. n JM, Granadino B, Beltran-Valero de 3 Fernandez-Ca~ no Bernabe D et al. (1996) The molecular basis of alkaptonuria. Nat Genet 14, 19. 4 Russo P, O’Regan S (1990) Visceral pathology of hereditary tyrosinemia type I. Am J Hum Genet 47, 317. 5 La Du BN (1995) Alkaptonuria. In: Scriver CR, Beaudet AL, Sly W, Valle D (eds), The Metabolic and Molecular Bases of Inherited Disease, 7th edn. p.1371, McGraw-Hill, New York. 6 O’Brien WM, La Du BN, Bunim JJ (1963) Biochemical, pathological and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropathy. Am J Med 34, 813–38. 7 Watts RW, Watts RA (2007) Alkaptonuria. A 60-year follow up. Rheumatology (Oxford) 46, 358–9. 8 La Du BN (2001). Alkaptonuria. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease. 8th edn, pp 2109–23. McGraw-Hill, New York, NY. 9 Phornphutkul C, Introne WJ, Perry MB et al. (2002) Natural History of alkaptonuria. N Engl J Med 347, 2111–21. 10 Milch RA (1960) Studies of Alcaptonuria: Inheritance of 47 Cases in Eight Highly Inter-related Dominican Kindreds. Am J Hum Genet 12, 76–85. 11 Zatkova A, Chmelikova A, Polakova H, Ferakova E, Kadasi L (2003) Rapid detection methods for five HGO gene mutations causing alkaptonuria. Clin Genet 63, 145–9. 12 Chevez Barrios P, Font RL (2004) Pigmented conjunctival lesions as initial manifestation of ochronosis. Arch Ophthalmol 122, 1060–3. 13 Mannoni A, Selvi E, Lorenzini S et al. (2004) Alkaptonuria, ochronosis, and ochronotic arthropathy. Semin Arthritis Rheum 33, 239–48.
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14 Introne WJ, Perry MB, Troendle J et al. (2011) A 3-year randomized therapeutic trial of nitisinone in alkaptonuria. Mol Genet Metab 103, 307–14. 15 Ludwig GD, Toole JF, Wood JC (1963) Ochronosis from quinacrine (atabrine). Ann Intern Med 59, 378–84. 16 Suwannarat P, Phornphutkul C, Bernardini I, Turner M, Gahl WA (2004) Minocycline-induced hyperpigmentation masquerading as alkaptonuria in individuals with joint pain. Arthritis Rheum 50, 3698–701. 17 Skinsnes OK (1948) Generalized ochronosis; report of an instance in which it was misdiagnosed as melanosarcoma, with resultant enucleation of an eye. Arch Pathol (Chic) 45, 552–8. 18 Wolff JA, Barshop B, Nyhan WL et al. (1989) Effects of ascorbic acid in alkaptonuria: alterations in benzoquinone
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19
20 21
22
acetic acid and an ontogenic effect in infancy. Pediatr Res 26, 140. Spencer JM, Gibbons CL, Sharp RJ, Carr AJ, Athanasou NA (2004) Arthroplasty for ochronotic arthritis: no failure of 11 replacements in 3 patients followed 6–12 years. Acta Orthop Scand 75, 355–8. Anikster Y, Nyhan WL, Gahl WA (1998) NTBC and alkaptonuria. Am J Hum Genet 63, 920–1. Suwannarat P, O’Brien K, Perry MB et al. (2005) Use of nitisinone in patients with alkaptonuria. Metabolism 54, 719–28. Aliberti G, Pulignano I, Pisani D, Rocchietti March M, Del Porto F, Proietta M (2007) Bisphosphonate treatment in ochronotic osteoporotic patients. Clin Rheumatol 26, 729–35.
International Journal of Rheumatic Diseases 2014; 17: 327–332
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
ORIGINAL ARTICLE
Alkaptonuric ochronosis: a clinical study from Ardabil, Iran Ahad AZAMI, Nasrollah MALEKI and Zahra TAVOSI Department of Internal Medicine, Imam Khomeini Hospital, Ardabil University of Medical Sciences, Ardabil, Iran
Abstract Objective: Ochronosis is a term used to describe pigment deposition that occurs in the connective tissues of patients with alkaptonuria, an autosomal recessive disorder that results from a deficiency of homogentisic acid oxidase. Brown or blue-gray discoloration of the skin may be seen on the axillary and inguinal areas, face, palms or soles. In addition, blue-black discoloration can be apparent on skin overlying cartilage in which the pigment is deposited, such as the ears. The sclerae are also typically involved. The cheapest screening test to perform prior to expensive lab tests is the urine oxidation test: having it standing in light for a period of 24 h when suspicion has risen. Methods: Retrospective analysis of patients with ochronotic arthropathy seen between September 2011 to September 2013 was carried out. Results: Seven patients (four male, three female) with ochronotic arthropathy were seen, their mean age was 46.1 years. All patients had bluish-black pigmentations of the ear cartilage and sclera. Spondylosis was seen in all, whereas peripheral arthritis was present in five patients. Moderate aortic insufficiency and calcification of the aortic valve was detected in one male patient. Urine screening for homogentisic acid was positive in all seven patients. Conclusion: Alkaptonuria is a rare autosomal recessive disorder of the metabolism caused by deficiency of homogentisic acid oxidase. It is suggested that more widespread screening should be undertaken in order to assess the true incidence of the disorder. Key words: alkaptonuria, homogentisic acid, ochronosis, spondylosis.
INTRODUCTION Ochronosis is an autosomal recessive disorder that results from deficient activity of homogentisic acid dioxygenase (HGD), the third enzyme in tyrosine degradation.1 The description of alkaptonuria by Garrod in 1902 led to recognition of the concept of a single enzyme deficiency resulting in lifelong disease.2 The gene encoding HGD has been mapped to chromosome 3q21-q23 and mutations have been identified in patients with ochronosis.3 Affected patients usually are asymptomatic in childhood. During the third decade, Correspondence: Dr Nasrollah Maleki, Department of Internal Medicine, Imam Khomeini Hospital, Ardabil University of Medical Sciences, Ardabil, Iran. Email: [email protected]
deposits of the brownish or bluish pigment become apparent, typically first in the ear cartilage and sclerae. Additional pigment is deposited in the large joints and the spine, especially the lumbosacral region. Calcification of multiple intervertebral discs is a characteristic radiographic finding. Axillary and inguinal areas may have a brownish discoloration. Perspiration can stain clothing in affected patients.4 Ochronosis is characterized by the excretion of urine that appears normal when fresh, but turns dark brown or black if left standing or after alkalinization. The dark color is caused by oxidation of homogentisic acid (HGA), and alkaptonuria has also been called black urine disease. Cloth diapers that are washed in alkaline solutions will have dark brown staining. The diagnosis is confirmed by quantitative measurement of HGA in urine.5
© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd
A. Azami et al.
MATERIALS AND METHODS This study was a retrospective analysis of patients presenting with ochronotic arthopathy from September 2011 to September 2013. All patients with spinal stiffness, peripheral arthritis, limited joint mobility and pigmentation in connective tissues were screened for urinary homogentisic acid and if found positive were diagnosed to have ochronotic arthropathy. Complete blood count (CBC), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serum calcium, phosphorus, alkaline phosphatase, rheumatoid factor and human leukocyte antigen (HLA)-B27 examinations were performed. X-rays of knees, spines, pelvis and sacroiliac joints were taken. Cardiac and pulmonary evaluation included clinical examination, chest X-ray, high-resolution computed tomography (HRCT) of the lungs, electrocardiogram and echocardiogram. Joint swelling, tenderness and range of motion were assessed. Schober’s test, chest expansion, occiput to wall distance and finger to floor distance were measured. Screening was done for ochronosis at various sites such as the ear, eye and skin. Family history of alkaptonuria or ochronosis was recorded.
RESULTS
Figure 1 Bluish-black pigmentations of the ear cartilage and antihelix.
Figure 2 Dark pigmentation of the sclera in the interpalpabral fissures.
In the 3 years of the study period, seven patients (four male, three female) with ochronotic arthropathy were identified. Their average age was 46.1 years. Table 1 shows the demographic data of the patients. All patients had symptoms of low backache, spinal stiffness and inability to bend. On physical examination, all patients had bluish-black pigmentations of the ear cartilage and antihelix (Fig. 1), and dark pigmentation of the sclera on both eyes in the interpalpabral fissures (Fig. 2). Bluish-black discoloration on the lateral sides of the fingers was visible in six patients (Fig. 3) and dark
pigmentation of the nail beds was seen in one patient (Fig. 3). Inflammatory markers, calcium, phosphorus, alkaline phosphatase, rheumatoid factor and HLA-B27 were normal in all patients. The urine turned black on exposure to air for 6 h in all patients (Fig. 4). Peripheral arthritis occurred in five patients. Joints involved were knees in five patients, ankles in one and hip in two patients. Symptoms were pain, stiffness and limited mobility of the involved joints in all patients. On
Table 1 Demographic data of the patients Patients
Age (years)
Gender
Pigmentation of the sclera
Pigmentation of the ears
Pigmentation of the fingers
Peripheral arthritis
Spondylosis
Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7
43 49 48 45 64 32 42
Male Male Female Female Female Male Male
+ + + + + + +
+ + + + + + +
+
+ + + +
+ + + + + + +
328
+ + + + +
+
Cardiac involvement
+
International Journal of Rheumatic Diseases 2014; 17: 327–332
Alkaptonuric ochronosis
Figure 3 Bluish-black discoloration on the lateral side of the fingers and nail beds.
Figure 4 Urine turned black on exposure to air.
X-rays, sacroiliac joints were normal in all the patients, whereas dorso-lumbar spine showed loss of lordosis, osteophytes and wafer-like calcification of intervertebral discs in all patients (Fig. 5). Pulmonary evaluation was normal in all patients. Moderate aortic insufficiency and calcification of the aortic valve was detected in one male patient. Measurement of urinary organic acid levels showed a large quantity of homogentisic acid in all patients, which was consistent with a diagnosis of ochronosis. Treatment with nitisinone, vitamin C and dietary restrictions of food containing phenylalanine and tyrosine had proved to be successful in alleviating symptoms.
DISCUSSION Ochronosis is a rare autosomal recessive condition that is caused by deficiency of homogentisate 1,2-dioxygenase, an enzyme that converts HGA to maleylacetoacetic
International Journal of Rheumatic Diseases 2014; 17: 327–332
acid in the tyrosine degradation pathway.6 This disease was first described by Garrod in 1902.2 The deficient enzyme was identified by La Du et al.7 in 1958. At least 1000 cases of ochronosis have been described; this is likely an underestimate.8 The incidence of this disease in the USA is 1 in 250 000 to 1 in 1 000 000 live births.9 Alkaptonuria occurs worldwide; a high prevalence has been observed in the Dominican Republic.10 The prevalence of alkaptonuria in Slovakia is estimated at 1 : 19 000.11 Alkaptonuria has three major features: 1) HGA in the urine. Oxidation of HGA excreted in the urine produces a melanin-like product and causes the urine to turn dark upon standing. 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 individuals never observe any abnormal color to their urine. 2) 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. Pigment deposition may also be seen in the conjunctiva and cornea. The pigmentation does not affect vision.12 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. Calcification of the ear cartilage may be observed on radiographs. Pigment also appears in cerumen and in perspiration, causing discoloration of clothing. A deep purple or black discoloration may be seen on the skin of the hands, corresponding to the underlying
329
A. Azami et al.
Figure 5 X-rays showing loss of lordosis, osteophytes and wafer-like calcification of intervertebral discs.
tendons, or in the web between the thumb and index finger. 3) Arthritis. This often begins in the spine and resembles ankylosing spondylitis in its large-joint distribution. 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 wafer-like calcification of the intervertebral ligaments also occur. Radiographs of the large joints may show joint space narrowing, subchondral cysts and osteophyte formation. Enthesopathy can be seen at the muscle insertions.13 The presence of any of these features should prompt confirmatory biochemical testing. The cheapest screening test to perform prior to expensive lab tests is the urine oxidation test: having it standing in light for a period of 24 h when suspicion has risen. The diagnosis of alkaptonuria is based on the detection of a significant amount of HGA in the urine by gas chromatography-mass spectrometry analysis. The amount of HGA excreted per day in individuals with alkaptonuria is usually between 1–8 g.8 A normal 24-h urine sample contains 20–30 mg of HGA.14 The natural history of ochronosis was evaluated in a study of 58 patients, ages 4–80 years.9 Arthropathy was common, and one-half of the patients had replacement of one knee, hip or shoulder before 55 years of age.
330
Renal stones developed in 16 patients (27%), at a mean age of 64 years. The mean ages for detection of cardiac valve involvement and coronary artery calcification were 54 and 59 years, respectively. In the natural history study cited above, ochronosis was diagnosed before 1 year of age in 12 of 58 patients (21%). In the remaining patients, the mean age at diagnosis was 29 years. Levels of HGA are increased in blood, urine and tissue samples.9 Ochronosis resulting from alkaptonuria may be confused with acquired, reversible pigmentary changes following prolonged use of carbolic acid dressings for chronic cutaneous ulcers.8 Chemically induced ochronosis has also been described following long-term use of either the antimalarial agent Atabrineâ (quinacrine),15 the skin-lightening agent hydroquinone, or the antibiotic minocycline.16 In one case of alkaptonuria, the ochronotic pigment in the eye was misdiagnosed as melanosarcoma, resulting in enucleation of the eye.17 The arthritis of alkaptonuria resembles ankylosing spondylitis in its damage to the spine and large joints, although it differs in sparing the sacroiliac joint and in its radiographic appearance. Radiographic findings of the spine also differentiate alkaptonuria from rheumatoid arthritis and osteoarthritis. No effective therapy is available for ochronosis. Dietary restriction of tyrosine and phenylalanine will reduce the excretion of HGA, although the clinical effect is limited.18
International Journal of Rheumatic Diseases 2014; 17: 327–332
Alkaptonuric ochronosis
Joint pain is substantial in individuals with alkaptonuria, and close attention to pain control is necessary. Optimal pain management should be tailored to the individual with close follow-up and long-term management. Physical and occupational therapy are important to promote optimal muscle strength and flexibility. Knee, hip and shoulder replacement surgeries are options for managing significant arthritis. In general, the goal of joint replacement is pain relief rather than increased range of motion. Joint replacement in individuals with alkaptonuria is associated with prosthetic survival comparable to that found in individuals with osteoarthritis.19 Pharmacologic treatment of alkaptonuria with oral administration of 2-(2-nitro-4-trifluoromethylbenzoyl)1,3-cyclohexanedione (NTBC) or nitisinone has been proposed.20 Nitisinone is a triketone herbicide that inhibits 4-hydroxyphenylpyruvate dioxygenase, the enzyme that produces HGA. Nitisinone is approved for the treatment of tyrosinemia type I. Nitisinone reduced urinary HGA excretion by at least 69% in two individuals, but at the expense of an elevated plasma tyrosine concentration.9 The only known side effects are elevated plasma tyrosine concentration resulting in photophobia and, rarely, corneal crystals. In a pilot study, low-dose nitisinone reduced urinary HGA by up to 95% in nine individuals with alkaptonuria. In the same study, seven individuals were treated for up to 15 weeks with nitisinone while receiving normal protein intake; all had elevated plasma tyrosine concentrations. No ophthalmic, neurologic or severe dermatologic complications were observed. Two individuals had transient elevations in liver transaminase levels that returned to normal after stopping nitisinone.21 In a 3-year therapeutic trial, 2 mg of nitisinone daily reduced urine and plasma HGA by 95% throughout the study duration.14 Plasma tyrosine averaged 800 lmol/L without dietary restriction. Side effects were minimal. One affected individual developed corneal crystals that required discontinuation of nitisinone and one affected individual had elevated liver transaminases. High-dose vitamin C decreases urinary benzoquinone acetic acid, a derivative of HGA, but has no effect on HGA excretion.18 It has been hypothesized that highdose ascorbic acid may prevent the deposition of ochronotic pigment, although it does not alter the basic metabolic defect.18 No credible studies have demonstrated the clinical efficacy of ascorbic acid.8 Oral bisphosphonate therapy has been suggested to halt the progressive bone loss; however, a prospective
International Journal of Rheumatic Diseases 2014; 17: 327–332
study of four affected individuals failed to demonstrate benefit.22
CONCLUSION Alkaptonuria is a rare autosomal recessive disorder of metabolism caused by deficiency of homogentisic acid oxidase and resulting in accumulation of homogentisic acid in collagenous structures. This causes the classic clinical triad: (i) homogentisic aciduria; (ii) ochronosis; and (iii) arthritis, usually in the fourth decade of life. It is suggested that more widespread screening should be undertaken in order to assess the true incidence of the condition.
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Copyright of International Journal of Rheumatic Diseases is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
