Rheumatol Int (2005) 25: 81–85DOI 10.1007/s00296-004-0498-1 R EV IE W Julie M. Keller Æ William Macaulay Ohannes A. Nercessian Æ Israeli A. Jaffe New developments in ochronosis: review of the literature Received: 2 April 2004 / Accepted: 11 June 2004 / Published online: 21 August 2004 Ó Springer-Verlag 2004 Abstract Ochronosis commonly affects all connective tissue. Recognition of changes secondary to the deposition of ochronotic pigments has increased with advances in diagnostic technology, allowing both improved imaging and early biochemical and genetics-based diagnosis of alkaptonuria, the cause of ochronosis. Successful symptomatic treatment of ochronotic arthropathy with joint replacement has been documented, and a new pharmacotherapeutic agent, nitisinone, is currently under investigation for both prevention and treatment of ochronosis. This review of the literature highlights recently recognized complications, new diagnostic techniques, and treatment options. Keywords Alkaptonuria Æ Arthrosis Æ Connective tissue manifestations Æ Diagnosis Æ Ochronosis Æ Review Introduction Ochronosis is the connective tissue manifestation of alkaptonuria, a defect in the metabolism of homogentisic acid (HGA) caused by autosomal recessive muta- No grants or industrial support were received for this investigation J. M. Keller Æ W. Macaulay Æ O. A. Nercessian Department of Orthopedic Surgery, Columbia University Medical Center, New York, NY, USA I. A. Jaffe Division of Rheumatology, Columbia University Medical Center, New York, NY, USA W. Macaulay (&) Center for Hip and Knee Replacement, 622 West 168 Street, PH1146, New York, NY 10032, USA E-mail:
[email protected] Tel.: +1-212-305-6959 Fax: +1-212-305-4024 tions of the HGO gene on chromosome 3q. Homogentisic acid is a metabolic product of phenylalanine and tyrosine; it accumulates in patients with alkaptonuria, polymerizing to form a dark pigment that is selectively deposited in connective tissues. These tissues become weak and brittle, developing cracks and chips and leading to chronic inflammation, degeneration, and osteoarthritis [1]. The condition is rare, affecting one in 250,000–1 million people, but can lead to serious disability [2, 3]. The most common presentations include: – Darkening of urine with exposure to air or reducing agents – Dark pigmentation of the pinna, sclera, and nasal ala – Narrowing of joint spaces and disc calcifications, primarily in the dorsolumbar spine, porotic vertebral bodies; osteophyte and bone bridge formation. These lead to lower back pain and stiffness, loss of lumbar lordosis, exaggerated thoracic kyphosis, and loss of height [4] – Hip and knee pain due to cartilage degeneration, joint space narrowing, and sclerosis with minimal osteophytic changes – Cardiac valve calcification and stenosis, coronary artery calcifications [5, 6] – Renal and prostatic stones While these manifestations have long been recognized, new techniques allow the diagnosis of other connective tissue manifestations of alkaptonuria that often constitute the seminal presentation of ochronosis. In addition, advances in the understanding of the genetic basis of the disease, its mechanism of action, and its implications have led to new methods of diagnosis and new questions regarding treatment. Mechanism of disease Connective tissues including hyaline cartilage, tendons, ligaments, and muscles are affected by the deposition of Other evidence suggests that it is not HGA itself but a byproduct of its oxidation that causes degeneration. The final result of the ochronotic process is weak connective tissue that chips and fractures. but decreased activity has been found in patients with ochronosis. relatively anaerobic environment of the body. as is characteristic of degenerative disease [5]. disc space narrowing. altering the cross-linking structure of the tissue (Fig. In one large study. free radicals are associated with tissue damage and are thought to cause degeneration by inciting inflammation. 8]. Connective tissue changes The consequences of these connective tissue changes were recognized long before any idea of the disease mechanism was understood. the surrounding bone usually appears unaffected [9]. Oxidation also leads to free radical formation. HGA can bind to connective tissue (CT) macromolecules. HGA polyphenol oxidase. an enzyme found in skin and connective tissue cells. partially due to the increased use of MRI. Spinal changes pathognomonic for ochronosis include severe disc calcification. It is also possible that HGA physically binds to connective tissue and alters the structure and interactions of the macromolecules [7]. while joint space narrowing and sclerosis are characteristic. Ochronotic pigment forms as patients grow older and kidney functions slow. There are several theories as to how alkaptonuria results in ochronosis and the associated connective tissue changes (Fig. The tissues become weak. where the environment is alkaline and aerobic. tears of anterior cruciate and ankle ligaments [10].82 ochronotic pigment. and rupture of the patellar and Achilles tendons during normal activity or . particularly the knees and hips. Finally. it is oxidized to benzoquinoneacetate (BQA). but as kidney function decreases with age. a cartilage enzyme required for the formation of hydroxylysine residues that are essential for cross-linking. This oxidation occurs spontaneously in urine. Relentlessly progressive arthropathy is characteristic of ochronosis. polymerized BQA. brittle. found mainly in the liver and kidneys. is required to catalyze the reaction. allowing for the accumulation of HGA. Ochronotic arthritis differs from other forms of arthritis in that. Thickened Achilles tendons. the majority of patients involved were found to have tendon-related findings on MRI. which is polymerized to the pigment by unknown mechanisms. 1). The HGA may act as a chemical irritant. osteophytic changes are not as evident. and sclerosis. Its oxidative product benzoquinoneacetic acid (BQA) is also formed. causing inflammation and more rapid degeneration of the joints. leading to further inflammation and exacerbating the existing problem [7]. As HGA accumulates both inter. cracking. changing the structural integrity of the CT. Absence of the enzyme homogentisic acid oxidase. Also unique is that articular cartilage of the synovial joints. and prone to chipping. leading to free radical formation and inhibition of lysyl hydroxylase and tissue damage leading to degeneration such as that seen with rheumatoid arthritis [8]. Fig.and intracellularly. 1) [7. leading to rapid degeneration of the joints. and rupture. HGA can be excreted by the kidneys. It is thought that BQA. or a melanin-like pigment formed from BQA forms chemical bonds to connective tissue macromolecules. In the neutral. it accumulates. 1 Alkaptonuria and ochronosis. Changes occur primarily in the dorsolumbar spine rather than the lumbosacral spine. is often found to be completely black and very brittle. It is not clear how this inhibition occurs. the structural integrity of the tissue may decrease due to inhibition of lysyl hydroxylase. Other connective tissue changes have been increasingly recognized. leads to the accumulation of homogentisic acid (HGA). osteophytosis. It is unclear whether the nature of the disease has changed or whether our tools to detect these changes have just improved. Quadriceps and hamstring muscle tears due to minimal trauma. deposition of ochronotic pigment discretely localized to the area of rupture has been observed. allowing for normal healing and bone growth once the ochronotic depositions are removed [3. it is much more likely that a patient’s connective tissue symptoms could be accurately attributed to ochronosis. the abnormalities in metabolism lead to higher urinary excretion of type I collagen N-telopeptide. Recent studies have found that late shoulder involvement is common and identified several novel presentations involving the upper extremity. allowing for definitive diagnosis of alkaptonuria before it presents symptomatically as ochronosis. upper extremity involvement in ochronosis has been identified as a rare. proximal interphalangeal. Alkaptonuria is caused by a mutation to the HGO gene. New techniques have been developed for rapid detection of five of these mutations which could allow easy recognition of the condition before symptoms occur [16]. Such cases are unusual in that disc herniation occurred without prior disc calcification. and knee. which is usually an early manifestation of disease. In the past. and it is likely that herniation occurred due to weakening of the cartilage by pigment deposition. 9]. and narrowing and sclerosis in the shoulders and DIP joints [5].83 with minimal trauma [3] have all been identified. wrist. Earlier case studies have reported pigmentation of the flexor digitorum profundus [13]. asymptomatic supraspinatus tears [11]. located on chromosome 3q. Diagnosis While it is true that the diversity of presentation in ochronosis has seemingly increased. In the case of ruptures and tears. In addition to the possible clinical implications of increased bone loss. carpalmetacarpal and distal interphalangeal (DIP) joints [2]. with histories of spinal changes and multiple lower extremity joint involvement progressing to include shoulder pain. though many patients require multiple joint replacement or remain debilitated secondary to back or other joint pains. and frameshift mutations and splice site abnormalities [10]. Ultrasound and X-ray detect renal and prostatic stones. and metacarpophalangeal synovitis have also been observed [10]. shoulder. degenerative changes. The intervertebral discs were all found to contain black material on discectomy. Sometimes the nearby articular cartilage was also noted to have ochronotic changes. Treatment options Currently. Elbow. often to significant debilitation [18]. Magnetic resonance imaging shows thickened tendons and asymptomatic tears. much as weakening of tendons and ligaments occurs. improving prognostic predictions and allowing for proper education and definitive treatment of the joint pain. Case studies have included patients presenting with symptoms including joint space narrowing. late complication of the disease. and pigment deposition of hand tendon sheaths and knuckle pads [12]. It is thought that the successes of joint replacement and tendon repair are due to the structural integrity of the surrounding tissue. Homozygous and compound heterozygous loss of function mutations have been described and vary in prevalence. depending on the population. Pigment deposition was highly localized and discectomy results were excellent in all cases [4]. symptomatic treatment of the complications of alkaptonuria is the only option. Patients usually presented in their 40s to 50s. Lumbar disc herniation has also been observed in case studies as the presenting symptom of ochronosis. New molecular diagnostic techniques are also being increasingly employed. Ochronosis leading to degenerative joint disease has been treated with exercise and analgesics but inevitably progresses. Preventative treatment of bone loss could be instigated prior to the development of severe osteopenia or osteoporosis [17]. and with the diagnosis of alkaptonuria. decreased range of motion. Tendon ruptures due to ochronosis have been fixed successfully with primary repair [3]. Alleviation of pain and significant increases in activity have been achieved with total joint replacement of both the hips and knees [19]. Forty mutations have been found involving 106 of the 114 alleles of this gene. Measurements of this value could aid in early. and hand joint involvement were uncommonly recognized [11]. nonsense. including missense. The implications for joint replacement . and DIP joints [12]. it is thought that mutations vary by the origin of the population and have been distributed according to human migration patterns [15]. convenient diagnosis of the condition. Echocardiogram and CT have allowed detection of coronary artery calcifications and cardiac valve defects. These studies together suggest that upper extremity involvement is not uncommon but perhaps commonly unrecognized or incorrectly attributed to other disease processes. ankle. it should also be noted that advances in technology have promoted the detection of many manifestations that would have remained unseen in early studies. making this an imperfect solution [9]. sclerosis and small osteophyte formation of the shoulder. Outcomes have been successful with both cemented and cementless implants. One study of 64 patients aged 4 to 80 years with recognized ochronosis found several cases of synovitis of the metacarpophalangeal joints. Recent studies have also discovered an increase in bone resorption in patients with alkaptonuria. stenosing synovitis of the flexor tendons [14]. and sometimes calcifications of nearby tendons. Another case series identified patients in various stages of ochronosis with degenerative arthritis involving multiple upper extremity joints including all or some of the elbow. Bagis S. this action would cause direct pharmacological reduction of HGA production by inhibiting the tyrosine degradation pathway and. Pulignano I. J Inherit Metab Dis 26:17–23 16. Major P. Cooke TDV. Cullu E. but further investigations into the efficacy of this treatment are required. Yuksel-Apak M. The clinical effect of any of these treatments has been minimal. Demirkol M. Sur H (2000) Cementless total knee arthroplasty in ochronotic arthropathy: a case report with 4-year follow-up. Bernardini I. arthroscopic and pathologic findings. Holme E. J Neurosurg (Spine 1) 98:87–9 5. so that the toxic by-product HGA is not made. Preece MA. Pope JE (2002) Alkaptonuria with atypical joint involvement. Fitzpatrick DL et al (2002) Natural history of alkaptonuria. and renal and prostatic stones.84 and connective tissue repair of recent studies suggesting that ochronosis increases bone resorption have not yet been investigated. Romagnoli E. Cefle A. J Bone Joint Surg Br 85:883–6 4. This would prevent the accumulation of HGA and the occurrence of ochronosis. Steinman B (eds) Connective tissue and its heritable disorders: molecular. Bodur H. Nitisinone has been shown to significantly lower the urinary excretion of HGA in both murine models and humans. Rheumatol Int 21:205–9 19. Hunter T (1982) Tendon involvement in a case of ochronosis. Sahin G. though further studies are required to assess its efficacy and possible side effects. but the ocular effects of long-term treatment are unknown and complying with the dietary restriction necessary to prevent elevated tyrosine would be extremely difficult. and delayed development [7]. which is associated with neurological complications including tremor. Introne WJ. J Bone Joint Surg Br 52:653–65 7. Hassan B (1999) Ochronotic arthropathy: case report and review of the literature. pp 809–825 9. Standing S. theoretically. Rajasekaran S (2003) Spontaneous tendon ruptures in alkaptonuria. Farzannia A. can effectively treat existing ochronosis. Proietta M (2003) Bone metabolism in ochronotic patients. Akdeniz S. Alrehaily A. Borman P. genetic and medical aspects. This can be prevented by severe restriction of tyrosine and phenylalanine in the diet [21]. Nas K. Kumar RV. References 1. Orthop Rev 19:1005–9 . Uyguner O. Others have not shown such a reduction [10]. Other attempts at preventing complications have included diets low in tyrosine and phenylalanine. Int Orthop 23:122–5 6. Pata C. Perry MB. Ploechl E et al (2001) Outcome of tyrosinemia type III. Some studies have shown that these changes lower urine HGA excretion but do not prevent its accumulation and complications [19]. Gur A. whether by gene therapy or exogenous hormone. Seradge H (1981) Ochronotic stenosing flexor tenosynovitis. ligaments. New York. Kadasi L (2003) Rapid detection methods for five HGO gene mutations causing alkaptonuria. there is not yet evidence that treatment with nitisinone prevents ochronosis. reversible binding. Ciliz D (2002) Ochronotic arthropathy. It has the known side effect of elevating plasma tyrosine. Aliberti G. Phornphutkul C. Hadidchi S (2003) Alkaptonuria and lumbar disc herniation. Recognition of the changes secondary to deposition of ochronotic pigments has increased with advances in diagnostic technology allowing both improved imaging and early biochemical and genetics-based diagnosis of alkaptonuria. In: Royce RM. Nitisinone is a triketone herbicide that inhibits 4-hydrophenylpyruvate dioxygenase by rapid. Clin Rheumatol 21:170–2 12. Zatkova A. J Rheumatol 9:634–6 14. Schiappoli A. La Du B (2002) Alkaptonuria. The ideal would involve replacement of the missing enzyme. Treatment and prevention of ochronotic osteopenia are also in need of further study. Laskar FH. Ferakova E. Kayserili H. ataxia. Sarac AJ (2002) Ochronosis: a case of severe ochronotic arthropathy. Cevik R. Milcan A. as there are several unknowns regarding long-term results. Manganelli S. Harris CM (1990) Bilateral hip and bilateral knee arthroplasties in a patient with ochronotic arthropathy. Murphey MD. Sargison KD (1970) Ochronotic arthropathy: a review with four case reports. Baykal T. Rheumatol Int 21:78–80 3. Wollnik B (2003) Molecular analyses of the HGO gene mutations in Turkish alkaptonuria patients suggest that the R58 fs mutation originated from central Asia and was spread throughout Europe and Anatolia by human migrations. J Int Med 254:296–300 18. Clin Genet 63:145–9 17. seizure. Marcolongo R (2000) Chronic ochronotic arthritis: clinical. intellectual impairment. Conclusions Review of the literature suggests that ochronosis commonly affects all connective tissue and includes early changes in the upper extremity and small joints as well as decreased integrity of tendons. Goicoechea de Jorge E. Minisola S. or has any effect on bone metabolism. and increasing vitamin C intake to prevent oxidation to BQA and free radical formation [20]. N Engl J Med 347:2111–21 11. Aydogdu S. Nitisinone is the first pharmacotherapeutic agent that seems to prevent ochronosis. cardiac calcifications. Cefle K. leading to corneal irritation. Chmelikova A. Green A. J Arthroplasty 15:539–43 10. Carrier DA. Selvi E. Though questions remain. Erdogan C (2001) A case of ochronosis: upper extremity involvement. Nitisinone is FDA-approved for the treatment of tyrosinemia type I. Second edn. J Inher Metab Dis 24:824–32 8. Wiley-Liss. Nitisinone could also theoretically lead to the development of tyrosinemia type III. nitisinone is the first possibility for potent pharmacotherapy of ochronosis [20]. Harman M. Benucci M. Ellaway CJ. Symptomatic treatment of ochronotic arthropathy includes successful use of total joint replacement and primary repair of connective tissue damage. J Rheumatol 29:198–9 13. J Hand Surg 6:359–60 15. Rodriguez de Cordoba S. This therapy is not currently possible. Polakova H. Shokouhi G. MacKenzie CR. There is currently no preventative treatment for the complications of alkaptonuria that has proven efficacious. and muscles. Hamdi N. J Rheumatol 27:2272–4 2. would prevent HGA accumulation. Ozsoy MH. Kokturk A. 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