Clin Rheumatol DOI 10.1007/s10067-014-2557-7
CASE BASED REVIEW
Ochronotic arthropathy as a paradigm of metabolically induced degenerative joint disease. A case-based review L. Ventura-Ríos & C. Hernández-Díaz & L. Gutiérrez-Pérez & A. Bernal-González & R. Pichardo-Bahena & A. L. Cedeño-Garcidueñas & C. Pineda
Received: 15 February 2014 / Accepted: 23 February 2014 # Clinical Rheumatology 2014
Abstract Alkaptonuria is a rare, hereditary metabolic disorder in which a deficiency in the homogentisate 1,2dioxygenase enzyme results in an accumulation of homogentisic acid. Deposition of excess homogentisic acid in different intra- and extra-articular structures with high content of connective tissue causes brownish-black pigmentation and weakening, ultimately resulting in tissue degeneration and finally osteoarthritis. Ochronotic arthropathy is considered a rapidly progressive, disabling condition in which weightbearing joints and the thoracolumbar spine are predominantly affected. Patients often require multiple joint replacements, such as in the case of the patient presented here. At present, there is no definitive cure for ochronosis, and management is predominantly symptomatic. Keywords Alkaptonuria . Degenerative joint diseases . Ochronosis . Ochronotic arthropathy . Osteoarthritis Dear Editor, Alkaptonuria is a rare autosomal recessive disorder with an estimated prevalence that is found in the majority of populations [1]. It is caused by a deficiency of homogentisate 1,2
L. Ventura-Ríos : C. Hernández-Díaz : A. Bernal-González : C. Pineda (*) Musculoskeletal Ultrasound Laboratory, Instituto Nacional de Rehabilitación, Calzada México–Xochimilco 289, Col. Arenal de Guadalupe, Del. Tlalpan, 14389 México, D.F., Mexico e-mail: [email protected] L. Gutiérrez-Pérez Musculoskeletal Ultrasound Diploma Course, Instituto Nacional de Rehabilitación, Mexico City, Mexico R. Pichardo-Bahena : A. L. Cedeño-Garcidueñas Anatomical Pathology Service, Instituto Nacional de Rehabilitación, Mexico City, Mexico
dioxygenase (HGD), resulting in an accumulation of homogentisic acid (HGA) [2] and is clinically manifested by homogentisic aciduria, ochronosis, and ochronotic arthropathy. This disorder is caused by mutations in the HGD gene, which maps to human chromosome 3q21–q23 [1–3]. We describe the case of a male patient with alkaptonuria, manifested by all three components of the classic triad, who developed prominent manifestations of ochronotic arthropathy and that led him to develop disability. He was treated with multiple joint replacements and physical therapy, alleviating pain and restoring function. Additionally, we review and summarize the pertinent literature on this rare form of metabolic arthropathy. In 2008, a 60-year-old Mexican mestizo male underwent total left knee replacement due to severe osteoarthritis (OA). After surgery, the patient began complaining of mechanicaltype pain, stiffness, and instability of the right knee. On physical examination, bluish-gray pigmentation of the sclerae and skin pigmentation on the cartilage of the ears and fingers (Fig. 1) were noted. The urine slowly became dark when oxidized by exposure to atmospheric air. Right knee examination showed moderate effusion, with tenderness over the medial and lateral joint line, limitations for flexion and full extension, and positive ballotable patella and brush signs. There was no laxity of the collateral or cruciate ligaments. X-rays of the right knee showed advanced signs of OA, characterized by diffuse joint-space narrowing, subchondral sclerosis, and femoral, tibial, and patellar osteophytosis. Ultrasound (US) of the knee showed joint effusion, synovial hypertrophy, and osteophyte formation. Thoracolumbar Xrays showed multilevel disc calcifications and space narrowing (Fig. 2). Echocardiogram showed no abnormalities. Treatment with non-steroidal anti-inflammatory drugs (NSAID), glucosamine sulfate, and rehabilitative therapy yielded initial improvement; however, the patient later
Clin Rheumatol Fig. 1 Bluish-brown discoloration of the auricles, sclerae, and finger due to accumulation of homogentisic acid. 299x258mm (300 x 300 DPI)
developed persistent pain and functional limitation. Thus, in 2012, he underwent total joint replacement of the right knee. Macroscopically, the articular cartilage exhibited heavy blackish pigmentation that spared the bony surfaces.
Fig. 2 Imaging of ochronotic arthropathy. a) Knee ultrasound displaying large osteophytes and femorotibial joint space narrowing of the right knee. b) Knee x-rays showing advanced degenerative changes. c) Multilevel intervertebral disc space narrowing associated with disc calcifications of the thoracolumbar spine. 399x324mm (300 x 300 DPI)
Denuded cartilage areas showed eburnation and osteophyte formation. Histologically, sections stained with hematoxylin and eosin (H&E) showed full-thickness ocher pigmentation of the cartilage. The transitional zone between the cartilage and
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the subchondral bone was sharply demarcated and free of ochronotic pigment deposits. Chondrocytes were arranged normally. Ultrastructural examination by transmission electron microscopy showed slight disorganization of the collagen fibers of the territorial matrix. The majority of collagen fibers displayed a homogeneous appearance and retained their striated aspect. Some collagen fibers displayed small electrondense granules of ochronotic pigment within the fibers; additionally, extracellular matrix pigment deposits were observed (Fig. 3). A constructed genetic family tree disclosed that the patient comes from a region of high consanguinity and that he has a sister with alkaptonuria.
3. Ochronotic arthropathy, predominantly affecting hips, knees, and spine, representing the major cause of disability in alkaptonuria [2–5].
Ochronotic arthropathy
1. Homogentisic aciduria. Homogentisate 1,2-dioxygenase (HGD) deficiency causes excretion of large quantities of homogentisic acid (HGA) daily in the urine, which turns dark on standing by an oxidation process or induced when alkalinized 2. Ochronosis. As a result of HGA accumulation in tissues, with darkening of connective tissues, manifested as pigmentation of skin, sclera, cartilage, and cardiac valves.
Usually, joint symptoms start between the ages of 40 and 50 years. There is a predominance of men relative to women: 2:1 [6]. Both synovial and intervertebral joints are affected [7]. Clinical features include back and peripheral joint pain, limitation of movement, and stiffness. The arthropathy closely resembles OA, clinically presents a mechanical type of pain, and there is a minor inflammatory component; both conditions exhibit similar distribution of joint abnormalities and comparable morphostructural X-ray changes. Axial manifestations include flattening of the thoracic kyphosis and loss of lumbar lordosis, progressive kyphoscoliosis, disc prolapse that may result in spinal stenosis, and myelopathy [8]. Patients usually have complaints in major joints, such as shoulders, knees, and hips. Radiographic findings may precede the onset of symptoms [9]. There are oxidized HGA deposits in the deeper layers of the articular cartilage, being more pronounced in the senescent cartilage with poor metabolism; as a result, the cartilage loses its elasticity further and becomes brittle, developing poor biomechanical conditions. Consequently, the cartilage suffers from fragmentation and forms loose bodies. Some small cartilage fragments may adhere to the synovial membrane, causing thickening, fibrosis, and chondromatosis [10–12]. Large segments of cartilage may completely disappear, causing bony ankylosis. Additionally, osteophytes and subchondral cysts are formed.
Fig. 3 Macro-, Micro- and ultrastructure of ochronotic pigment a) Surgically removed portions of the femoral condyle and tibial plateaus showing heavy pigmentation of the articular cartilage, sparing the bone surfaces. b) Articular cartilage has brown ocher tint (white arrow) subchondral bone (double arrow) and trabecular
spaces (arrowheads) display normal staining affinity (4x, H & E). c) Fragmented collagen fiber with irregular contours (arrow) (39,000 x). d) Hemispherical electron-dense deposits (arrow) and e) irregular extracellular electron dense deposits. 399x189mm (300 x 300 DPI)
Review By the beginning of 2011, only 626 patients with alkaptonuria had been reported in about 40 countries worldwide [1]. As a result of this rare, inherited metabolic disorder, the following classic clinical triad of alkaptonuria may develop:
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As a result of HGA oxidation, free radicals are produced and are associated with tissue damage caused by the induction of both inflammatory and degenerative processes [13]. The structural integrity of the tissues may decrease due to the inhibition of lysyl hydroxylase, a cartilaginous enzyme required for the formation of hydroxylysine residues, which are essential for crosslinking; however, how inhibition occurs is not clear [14]. Ocher granular deposits are observed in all layers of hyaline cartilage. Cartilage cells may become small and pyknotic. Fibrocartilage may show areas of degeneration and calcification. The perichondrium may be thickened and pigmented. The synovium becomes thick with deposits of granules and may have calcifications and focal islets of cartilage [15]. Tendons are also sites of ochronotic pigment deposition because of their high collagen content. Several cases of spontaneous tendon and ligament ruptures have been reported [16, 17]. Patellar and Achilles tendon are the most affected [18, 19]. Filippou et al. studied the flexor and extensor apparatus of the upper and lower limbs in seven patients with ochronosis by US. The first distinctive feature was lack of involvement of the tendons with synovial sheaths; however, the insertion site of the traction tendons was affected (thickening and reduced echogenicity of insertional tract and, in some cases, power Doppler signal), resembling the changes of enthesopathy [20]. Moreover, patients may develop osteopenia and increased risk for fracture [7].
Table 1 Radiographic abnormalities of ochronotic arthropathy Axial involvement Vertebral-body osteoporosis Intervertebral discal calcification Intervertebral disc space narrowing with vacuum phenomena Small or absent osteophytosis Loss of lumbar lordosis Peripheral joint distribution and involvement Involvement of sacroiliac joints, symphysis pubis, and large peripheral joints (hips, knees, shoulders) Joint-space narrowing Bony eburnation Collapse and fragmentation (osteochondral loose bodies) Small osteophytes Tendon involvement with ruptures or calcifications
propensity for the lumbar spine, followed by the thoracic and cervical segments [23]. Additionally, multilevel intervertebral disc space narrowing associated with a radiolucent collection of gas (vacuum phenomena) are characteristic findings. Bony eburnation of contiguous vertebral bodies and small osteophyte formations also are suggestive of this diagnosis [24]. In long-standing disease, severe changes may appear, leading to progressive kyphosis, apophyseal joint abnormalities, disc space obliteration, and bony bridging simulating the spinal changes of ankylosing spondylitis (AS).
Radiographic features The extent, characteristics, and distribution of ochronotic arthropathy are largely documented by plain X-ray. Its pattern of involvement is mainly characterized by the presence of osteoarthritic-like changes of both the spine and the large synovial joints [21]. Thus, the radiographic manifestations of ochronotic arthropathy may be separated into axial and peripheral abnormalities (Table 1).
Axial involvement The disease initially involves only a short segment of the axial skeleton, usually the lumbar segment; with longer disease duration, it may involve the whole spine [22]. Widespread, thin, linear, wafer-like, intervertebral disc calcifications are the characteristic X-ray abnormality of the spine in ochronosis. Despite that the intervertebral disc may be diffusely calcified, the inner fibers of the annulus fibrosus are predominantly affected. These calcific deposits are composed of apatite crystals and are considered dystrophic in nature. Any segment of the axial skeleton may be involved; however, the distribution of disc calcifications possesses a
Differential diagnosis The combination of disc space narrowing, discal calcification, band-like ossification of the intervertebral disc, and kyphosis at the thoracolumbar junction may resemble abnormalities in AS [9]. Confusion between these two diseases is further accentuated by abnormalities in the sacroiliac joints, symphysis pubis, and appendicular large joints [25]. Table 2 summarizes the main differences among ochronotic arthropathy, AS, and OA. Disc calcifications must be distinguished from those of the following: AS, diffuse idiopathic skeletal hyperostosis (DISH), juvenile idiopathic arthritis, calcium pyrophosphate dehydrate crystal deposition disease (CPPD), Klippel-Feil syndrome, and congenital and acquired fusions of the spine [9]. Additionally, disc space loss, vacuum phenomena, vertebral-body sclerosis, and variable osteophytosis resemble the changes of intervertebral osteochondrosis, a form of degenerative disease of the axial skeleton. However, the diagnosis of ochronosis must be considered for any patient with multilevel vertebral-body disc involvement. Lumbar disc herniation has also been observed in case studies as the presenting symptom of ochronosis; it is hypothesized that herniation
Clin Rheumatol Table 2 Differential diagnosis. Ochronotic arthropathy, ankylosing spondylitis, and osteoarthritis*
Distribution of abnormalities
Ochronosis
Ankylosing spondylitis
Osteoarthritis
Spine+++ Knees+++ Hips++ Shoulders+
Spine+++ Knees+ Hips+
Spine+++ Knees++ Hips++ Hands+++
Sparse Dense/water like Common Broad Mild
None Mild to moderate Rare Thin+vertical Severe
Prominent Mild to moderate Rare None Mild to severe
Symmetrical or asymmetrical Scanty Prominent
Symmetrical
Asymmetrical space narrowing Prominent Sparse
Axial abnormalities Osteophytes Discal calcification Multiple vacuum discs Syndesmophytes Apophyseal joint disease Peripheral joints Joint-space loss
*Modified from Reference 21
Osteophytes Intra-articular osseous bodies, fragmentation
occurs due to weakening of the fibrocartilage by ochronotic pigment deposition [26]. The intervertebral discs containing black material on discectomy may be the first datum leading to diagnosis.
Peripheral joint involvement Involvement of the large peripheral joints usually occurs about 10 years after spinal changes in alkaptonuria. Based on the analysis of 26 patients with ochronotic arthropathy, it may be noted that the small joints were spared and the large joints were predominantly affected in the following order: knees, 64 %; shoulders, 43 %; and hips, 35 % [27]. Overall, the radiographic changes in the diarthrodial joints are reminiscent of those observed in primary OA, including joint-space narrowing, bony sclerosis, and osteophytosis. Certain findings (Table 2) in ochronotic arthropathy allow its differentiation from other conditions as follows: 1. Unusual sites of joint involvement. Severe glenohumeral joint disease resembling OA in the absence of significant trauma suggests the diagnosis of ochronosis. Likewise, advanced changes in the sacroiliac joints and symphyseal joints (joint-space narrowing and calcification) [28] may be a clue to the presence of ochronotic joint involvement. Conversely, involvement of the elbows, wrists, and small joints of the hands were uncommonly recognized in this metabolic disorder [29]. 2. Joint-space loss with an unusual pattern. Symmetrical joint-space narrowing in the hips and shoulders, along with isolated lateral femorotibial loss of knee joint space, is unusual for OA and is observed in ochronosis.
None None
3. Unusual bony sclerosis, fragmentation, and intra-articular loose (osteochondral) bodies [9]. Deposits of HGA deteriorate the formation and architecture of proteoglycans in the hyaline cartilage, leading to fragmentation and rapid, destructive arthropathy [30]. The rapid disappearance of the femoral head was initially reported in two cases of ochronosis [31]. This report was followed by several reports on rapidly progressive arthropathy of the hip joint [32–34]. In undiagnosed cases, severe arthropathy leads to a variety of surgical procedures; macroscopic inspection of the joint during surgery shows darkening of the cartilage or a “black joint,” immediately evoking the diagnosis of ochronosis [35]. The production of multiple, loose osteochondral bodies (calcified and ossified pea-sized, or even larger, bodies of diverse shape) is a particular characteristic of ochronotic arthropathy and is a sign of ochronotic chondromatosis [36]. Synovial fluid analysis is reported as non-inflammatory in nature [37]; interestingly, the effusions are yellowish in color, and this remains unchanged even after prolonged standing in air, suggesting a low concentration of HGA [5]. Osteophyte formation is variable and may not be a prominent feature of this metabolic disorder. Humeral and femoral head avascular necrosis may occur in ochronosis [12].
MRI and nuclear medicine techniques Magnetic resonance imaging (MRI) findings mirror the characteristic radiographic changes of ochronosis; uniform loss of intervertebral disc height with central intradiscal low T1 and T2 signals, corresponding to intradiscal calcification and multilevel disc prolapse, is characteristic [38]. Diffuse type 2
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modic (fatty) endplate changes are unusual. Ochronotic spine should be considered in the differential diagnosis when these changes are present. Nuclear medicine techniques provide useful information that can be incorporated into the disease severity assessment. A semiquantitative isotope bone scan score has been proposed, depending on the involvement of large joints. This remains to be validated in a suitable cohort of patients [39]. Other imaging techniques, such as ultrasonography, may be useful for assessing degenerative changes. To date, only isolated case reports showing joint effusion, synovial proliferation, and increased vascularization have been reported [37]. Post-mortem examination of an unsuspected case of alkaptonuria revealed, in addition to ochronotic pigment, extensive CPPD deposits in tracheal, costal, femoral, and patellar cartilage tissues [40].
Treatment Several strategies have been used with little success. Physical therapy can be helpful in some cases. High doses of vitamin C and a low-protein diet have not proven effective. Pain control by means of paracetamol, anti-inflammatory drugs, opioids, anticonvulsants, local anesthetics, gabapentin, acupuncture, and nerve block has been attempted [8]. Nitisinone selectively inhibits the 4-hydroxyphenyl-pyruvic acid oxidase enzyme and reduces the formation of HGA, may prevent morbidity if started before symptomatic stage, or may slow progression in patients beginning with symptoms [8]. In a mouse model, nitisinone completely inhibited ochronosis; however, it caused increased blood tyrosine, whose clinical translation is unknown [41]. The ideal treatment would be replacing the missing enzyme either as an enzymatic protein or replacing the gene. We consider ochronotic arthropathy as a model of metabolic degenerative joint disease, with a rapidly progressive course that culminates in joint replacement, particularly of weight-bearing joints. Disclosures All authors declare no conflicts of interest. Ventura-Ríos L. None. Hernández-Díaz C. None. Gutiérrez-Pérez L. None. Bernal-González A. None. Pichardo-Bahena R. None. Cedeño-Garcidueñas A. None. Pineda C. None.
References 1. Ranganath L, Taylor AM, Shenkin A, Fraser WD, Jarvis J, Gallagher JA, Sireau N (2011) Identification of alkaptonuria in the general
population: a United Kingdom experience describing the challenges, possible solutions and persistent barriers. J Inherit Metab Dis 34(3): 723–730 2. Phornphutkul C, Introne WJ, Perry MB, Bernardini I, Murphy M, Fitzpatrick D, Anderson PD, Huizing M, Anikster Y, Gerber LH, Gahl WA (2002) Natural history of alkaptonuria. N Engl J Med 347: 2111–2121 3. Milch RA (1960) Studies of alkaptonuria: inheritance of 47 genes in highly inter-related Dominican kindreds. Am J Hum Genet 12:76–85 4. Zatkova A (2011) An update on molecular genetics of Alkaptonuria (AKU). J Inherit Metab Dis 34:1127–1136 5. Groseanu L, Marinescu R, Laptoiun D, Botezatu I, Staniceanu F, Zurac S, Ionescu R (2010) A late and difficult diagnosis of ochronosis. J Med Life 3:437–443 6. Rovenský J, Urbánek T, Stančíková M (2012) The clinical picture of alkaptonuria and ochronosis. Reumatologia 4:324–335 7. Helliwell TR, Gallagher JA, Ranganath L (2008) Alkaptonuria— a review of surgical and autopsy pathology. Histopathology 53: 503–512 8. Ranganath R, Jarvis J, Gallagher J (2013) Recent advances in management of alkaptonuria. J Clin Pathol 66:367–373 9. Toth K, Lenart E, Janositz G, Takacs K (2003) Ochronotic arthropathy. Scand J Rheumatol 32(5):315–317 10. Laskar TH, Sarginson KD (1970) Ochronotic arthropathy—review of four cases. J Bone Joint Surg 52:653–655 11. Aliberti G, Pulignano I, Schiappoli A, Minisola S, Romagnoli E, Proietta M (2003) Bone metabolism in ochronotic patients. J Intern Med 254:296–300 12. Broman P, Bodur H, Ciliz D (2002) Ochronotic arthropathy. Rheumatol Int 21:205–209 13. La Du B (2002) Alkaptonuria. In: Royce RM, Steinman B (eds) Connective tissue and its heritable disorders: molecular, genetic and medical aspects. 2nd Ed. New York: Wiley-Liss, New York, pp 809–825 14. Ellaway CJ, Holme E, Standing S, Preece MA, Green A, Ploechl E, Ugarte M, Trefz FK, Leonard JV (2001) Outcome of tyrosinemia type III. J Inherit Metab Dis 24:824–832 15. Gandhi R, Bahri N, Parekh S, Chudasama S, Shah C, Darnia B (2010) Literature and MR findings in ochronosis. Gujarat Med J 65(1):39–46 16. Mannoni A, Selvi E, Lorenzini S, Giorgi M, Airo P, Cammelli D, Andreotti L, Marcolongo R, Porfirio B (2004) Alkaptonuria, ochronosis, and ochronotic arthropathy. Semin Arthritis Rheum 33: 239–248 17. O’Brien WM, La Du BN, Bunim JJ (1963) Biochemical, pathological and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropathy. Review of the world literature (1584–1962). Am J Med 34:813–838 18. Abate M, Schiavone C, Salini V, Andia I (2013) Occurrence of tendon pathologies in metabolic disorders. Rheumatology 52: 599–608 19. Shah N, Goveas D, Khadilkar M (2012) A case of patellar tendon avulsion in an ochronotic patient and a review of the literature. JCR Indian J Med Case Rep 1:7–10 20. Filippou G, Frediani B, Selvi E, Bertoldi I, Galeazzi M (2008) Tendon involvement in patients with ochronosis: an ultrasonographic study. Ann Rheum Dis 67:1785–1786 21. Byers Kraus V (2008) Ochronosis, Kashin-Beck disease and Mseleni joint disease. In: Hochberg MC (ed) Rheumatology, 4th edn. Elsevier, Spain, pp 1791–1801 22. Perry MB, Suwannarat P, Furst G, Gahl W, Gerber L (2006) Musculoskeletal findings an disability in alkaptonuria. J Rheumatol 33:2280–2285 23. Sahin G, Milcan A, Baðiþ A, Köktürk A, Pata C, Erdoğan C (2001) A case of ochronosis: upper extremity involvement. Rheumatol Int 21:78–80
Clin Rheumatol 24. Resnick D (2002) Alkaptonuria. In: Resnick D (ed) Diagnosis of one and joint disorders. 4th ed. Philadelphia, PA, USA: W.B. Saunders Company, Philadelphia, PA, USA, pp 1686–1691 25. Koçyigit H, Gürgan A, Terzioglu R, Gürgan U (1998) Clinical, radiographic and echocardiographic findings in a patient with ochronosis. Clin Rheumatol 17(5):403–406 26. Keller JM, Macaulay W, Nercessian OA, Jaffe IA (2005) New developments in ochronosis: review of the literature. Rheumatol Int 2:81–85 27. Takagi M, Ida H, Kobayashi S, Ishii M, Osanai T, Konttinen YT (2003) Ochronotic spondyloarthropathy: two case reports of progressive destructive changes in the hip. Mod Rheumatol 13:81–86 28. Azhar A, Khan R, Smyth H (2007) Ochronotic arthritis. Int J Shoulder Surg 1:77–80 29. Shimizu I, Hamada T, Khalpey Z, Miyanishi K, Hara T (2007) Ochronotic arthropathy: pathological evidence of acute destruction of the hip joint. Clin Rheumatol 26:1189–1191 30. Steinger U, Lagier R (1973) Combined anatomical and radiological study of the hip-joint in alkaptonuric arthropathy. Ann Rheum Dis 31:369–373 31. Lagier R (1980) The concept of osteoarthritic remodeling as illustrated by ochronotic arthropathy of the hip. An anatomic-radiological approach. Virchow Arch A Pathol Anat Histol 385:293–308 32. Lagier R, Baud CH, Lacotte D, Cunningham T (1988) Rapidly progressive osteoarthrosis of ochronotic origin. Am J Clin Pathol 90:95–102 33. Lequesne M (1993) Rapidly progressing destructive diseases of the hip. Ann Radiol (Paris) 36:62–64
34. Corra T, Zaccala M, Galante M (1995) Ochronotic arthropathy: rapidly destructive hip osteoarthritis associated with metabolic disease. Clin Rheumatol 14:474–477 35. Kruithof E, Baeten D, Veys EM, De Keyser F, Suykens S, De Wilde L, Verdonk R (2004) Case Number 29: Ochronosis: synovial histopathological characteristics. (Abstract). Ann Rheum Dis 6:130 36. Bayindir P, Yilmaz Ovali G, Pabuşçu Y, Temiz C, Duruoz T (2006) Radiologic features of lumbar spine in ochronosis in late stages. Clin Rheumatol 25:588–590 37. Iannuccelli C, Coari G, Mastantuono M, Osimani M, Valesini G, Di Franco M (2009) Joint and tendineous involvement in ochronosis: clinical history and imaging of a case. Clin Exp Rheumatol 27: 696–697 38. Hamdulay SS, Finegold J, Boyer L, Khanna M, Akmal M, Walker A, Kinderlerer A (2012) Clinical images: magnetic resonance imaging appearance of alkaptonuria. (Abstract). Arthritis Rheum 64:129 39. Vinjamuri S, Ramesh CN, Jarvis J, Gallagher JA, Ranganath LL (2011) Nuclear medicine techniques in the assessment of alkaptonuria. Nucl Med Commun 32:880–886 40. McClure J, Smith PS, Gramp AA (1983) Calcium pyrophosphate dihydrate (CPPD) deposition in ochronotic arthropathy. J Clin Pathol 36:894–902 41. Preston AJ, Keenan CM, Sutherland H, Wilson PJ, Wlodarski B, Taylor AM, Williams DP, Ranganath LR, Gallagher JA, Jarvis JC (2014) Ochronotic osteoarthropathy in a mouse model of alkaptonuria, and its inhibition by nitisinone. Ann Rheum Dis 73: 284–289
CASE BASED REVIEW
Ochronotic arthropathy as a paradigm of metabolically induced degenerative joint disease. A case-based review L. Ventura-Ríos & C. Hernández-Díaz & L. Gutiérrez-Pérez & A. Bernal-González & R. Pichardo-Bahena & A. L. Cedeño-Garcidueñas & C. Pineda
Received: 15 February 2014 / Accepted: 23 February 2014 # Clinical Rheumatology 2014
Abstract Alkaptonuria is a rare, hereditary metabolic disorder in which a deficiency in the homogentisate 1,2dioxygenase enzyme results in an accumulation of homogentisic acid. Deposition of excess homogentisic acid in different intra- and extra-articular structures with high content of connective tissue causes brownish-black pigmentation and weakening, ultimately resulting in tissue degeneration and finally osteoarthritis. Ochronotic arthropathy is considered a rapidly progressive, disabling condition in which weightbearing joints and the thoracolumbar spine are predominantly affected. Patients often require multiple joint replacements, such as in the case of the patient presented here. At present, there is no definitive cure for ochronosis, and management is predominantly symptomatic. Keywords Alkaptonuria . Degenerative joint diseases . Ochronosis . Ochronotic arthropathy . Osteoarthritis Dear Editor, Alkaptonuria is a rare autosomal recessive disorder with an estimated prevalence that is found in the majority of populations [1]. It is caused by a deficiency of homogentisate 1,2
L. Ventura-Ríos : C. Hernández-Díaz : A. Bernal-González : C. Pineda (*) Musculoskeletal Ultrasound Laboratory, Instituto Nacional de Rehabilitación, Calzada México–Xochimilco 289, Col. Arenal de Guadalupe, Del. Tlalpan, 14389 México, D.F., Mexico e-mail: [email protected] L. Gutiérrez-Pérez Musculoskeletal Ultrasound Diploma Course, Instituto Nacional de Rehabilitación, Mexico City, Mexico R. Pichardo-Bahena : A. L. Cedeño-Garcidueñas Anatomical Pathology Service, Instituto Nacional de Rehabilitación, Mexico City, Mexico
dioxygenase (HGD), resulting in an accumulation of homogentisic acid (HGA) [2] and is clinically manifested by homogentisic aciduria, ochronosis, and ochronotic arthropathy. This disorder is caused by mutations in the HGD gene, which maps to human chromosome 3q21–q23 [1–3]. We describe the case of a male patient with alkaptonuria, manifested by all three components of the classic triad, who developed prominent manifestations of ochronotic arthropathy and that led him to develop disability. He was treated with multiple joint replacements and physical therapy, alleviating pain and restoring function. Additionally, we review and summarize the pertinent literature on this rare form of metabolic arthropathy. In 2008, a 60-year-old Mexican mestizo male underwent total left knee replacement due to severe osteoarthritis (OA). After surgery, the patient began complaining of mechanicaltype pain, stiffness, and instability of the right knee. On physical examination, bluish-gray pigmentation of the sclerae and skin pigmentation on the cartilage of the ears and fingers (Fig. 1) were noted. The urine slowly became dark when oxidized by exposure to atmospheric air. Right knee examination showed moderate effusion, with tenderness over the medial and lateral joint line, limitations for flexion and full extension, and positive ballotable patella and brush signs. There was no laxity of the collateral or cruciate ligaments. X-rays of the right knee showed advanced signs of OA, characterized by diffuse joint-space narrowing, subchondral sclerosis, and femoral, tibial, and patellar osteophytosis. Ultrasound (US) of the knee showed joint effusion, synovial hypertrophy, and osteophyte formation. Thoracolumbar Xrays showed multilevel disc calcifications and space narrowing (Fig. 2). Echocardiogram showed no abnormalities. Treatment with non-steroidal anti-inflammatory drugs (NSAID), glucosamine sulfate, and rehabilitative therapy yielded initial improvement; however, the patient later
Clin Rheumatol Fig. 1 Bluish-brown discoloration of the auricles, sclerae, and finger due to accumulation of homogentisic acid. 299x258mm (300 x 300 DPI)
developed persistent pain and functional limitation. Thus, in 2012, he underwent total joint replacement of the right knee. Macroscopically, the articular cartilage exhibited heavy blackish pigmentation that spared the bony surfaces.
Fig. 2 Imaging of ochronotic arthropathy. a) Knee ultrasound displaying large osteophytes and femorotibial joint space narrowing of the right knee. b) Knee x-rays showing advanced degenerative changes. c) Multilevel intervertebral disc space narrowing associated with disc calcifications of the thoracolumbar spine. 399x324mm (300 x 300 DPI)
Denuded cartilage areas showed eburnation and osteophyte formation. Histologically, sections stained with hematoxylin and eosin (H&E) showed full-thickness ocher pigmentation of the cartilage. The transitional zone between the cartilage and
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the subchondral bone was sharply demarcated and free of ochronotic pigment deposits. Chondrocytes were arranged normally. Ultrastructural examination by transmission electron microscopy showed slight disorganization of the collagen fibers of the territorial matrix. The majority of collagen fibers displayed a homogeneous appearance and retained their striated aspect. Some collagen fibers displayed small electrondense granules of ochronotic pigment within the fibers; additionally, extracellular matrix pigment deposits were observed (Fig. 3). A constructed genetic family tree disclosed that the patient comes from a region of high consanguinity and that he has a sister with alkaptonuria.
3. Ochronotic arthropathy, predominantly affecting hips, knees, and spine, representing the major cause of disability in alkaptonuria [2–5].
Ochronotic arthropathy
1. Homogentisic aciduria. Homogentisate 1,2-dioxygenase (HGD) deficiency causes excretion of large quantities of homogentisic acid (HGA) daily in the urine, which turns dark on standing by an oxidation process or induced when alkalinized 2. Ochronosis. As a result of HGA accumulation in tissues, with darkening of connective tissues, manifested as pigmentation of skin, sclera, cartilage, and cardiac valves.
Usually, joint symptoms start between the ages of 40 and 50 years. There is a predominance of men relative to women: 2:1 [6]. Both synovial and intervertebral joints are affected [7]. Clinical features include back and peripheral joint pain, limitation of movement, and stiffness. The arthropathy closely resembles OA, clinically presents a mechanical type of pain, and there is a minor inflammatory component; both conditions exhibit similar distribution of joint abnormalities and comparable morphostructural X-ray changes. Axial manifestations include flattening of the thoracic kyphosis and loss of lumbar lordosis, progressive kyphoscoliosis, disc prolapse that may result in spinal stenosis, and myelopathy [8]. Patients usually have complaints in major joints, such as shoulders, knees, and hips. Radiographic findings may precede the onset of symptoms [9]. There are oxidized HGA deposits in the deeper layers of the articular cartilage, being more pronounced in the senescent cartilage with poor metabolism; as a result, the cartilage loses its elasticity further and becomes brittle, developing poor biomechanical conditions. Consequently, the cartilage suffers from fragmentation and forms loose bodies. Some small cartilage fragments may adhere to the synovial membrane, causing thickening, fibrosis, and chondromatosis [10–12]. Large segments of cartilage may completely disappear, causing bony ankylosis. Additionally, osteophytes and subchondral cysts are formed.
Fig. 3 Macro-, Micro- and ultrastructure of ochronotic pigment a) Surgically removed portions of the femoral condyle and tibial plateaus showing heavy pigmentation of the articular cartilage, sparing the bone surfaces. b) Articular cartilage has brown ocher tint (white arrow) subchondral bone (double arrow) and trabecular
spaces (arrowheads) display normal staining affinity (4x, H & E). c) Fragmented collagen fiber with irregular contours (arrow) (39,000 x). d) Hemispherical electron-dense deposits (arrow) and e) irregular extracellular electron dense deposits. 399x189mm (300 x 300 DPI)
Review By the beginning of 2011, only 626 patients with alkaptonuria had been reported in about 40 countries worldwide [1]. As a result of this rare, inherited metabolic disorder, the following classic clinical triad of alkaptonuria may develop:
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As a result of HGA oxidation, free radicals are produced and are associated with tissue damage caused by the induction of both inflammatory and degenerative processes [13]. The structural integrity of the tissues may decrease due to the inhibition of lysyl hydroxylase, a cartilaginous enzyme required for the formation of hydroxylysine residues, which are essential for crosslinking; however, how inhibition occurs is not clear [14]. Ocher granular deposits are observed in all layers of hyaline cartilage. Cartilage cells may become small and pyknotic. Fibrocartilage may show areas of degeneration and calcification. The perichondrium may be thickened and pigmented. The synovium becomes thick with deposits of granules and may have calcifications and focal islets of cartilage [15]. Tendons are also sites of ochronotic pigment deposition because of their high collagen content. Several cases of spontaneous tendon and ligament ruptures have been reported [16, 17]. Patellar and Achilles tendon are the most affected [18, 19]. Filippou et al. studied the flexor and extensor apparatus of the upper and lower limbs in seven patients with ochronosis by US. The first distinctive feature was lack of involvement of the tendons with synovial sheaths; however, the insertion site of the traction tendons was affected (thickening and reduced echogenicity of insertional tract and, in some cases, power Doppler signal), resembling the changes of enthesopathy [20]. Moreover, patients may develop osteopenia and increased risk for fracture [7].
Table 1 Radiographic abnormalities of ochronotic arthropathy Axial involvement Vertebral-body osteoporosis Intervertebral discal calcification Intervertebral disc space narrowing with vacuum phenomena Small or absent osteophytosis Loss of lumbar lordosis Peripheral joint distribution and involvement Involvement of sacroiliac joints, symphysis pubis, and large peripheral joints (hips, knees, shoulders) Joint-space narrowing Bony eburnation Collapse and fragmentation (osteochondral loose bodies) Small osteophytes Tendon involvement with ruptures or calcifications
propensity for the lumbar spine, followed by the thoracic and cervical segments [23]. Additionally, multilevel intervertebral disc space narrowing associated with a radiolucent collection of gas (vacuum phenomena) are characteristic findings. Bony eburnation of contiguous vertebral bodies and small osteophyte formations also are suggestive of this diagnosis [24]. In long-standing disease, severe changes may appear, leading to progressive kyphosis, apophyseal joint abnormalities, disc space obliteration, and bony bridging simulating the spinal changes of ankylosing spondylitis (AS).
Radiographic features The extent, characteristics, and distribution of ochronotic arthropathy are largely documented by plain X-ray. Its pattern of involvement is mainly characterized by the presence of osteoarthritic-like changes of both the spine and the large synovial joints [21]. Thus, the radiographic manifestations of ochronotic arthropathy may be separated into axial and peripheral abnormalities (Table 1).
Axial involvement The disease initially involves only a short segment of the axial skeleton, usually the lumbar segment; with longer disease duration, it may involve the whole spine [22]. Widespread, thin, linear, wafer-like, intervertebral disc calcifications are the characteristic X-ray abnormality of the spine in ochronosis. Despite that the intervertebral disc may be diffusely calcified, the inner fibers of the annulus fibrosus are predominantly affected. These calcific deposits are composed of apatite crystals and are considered dystrophic in nature. Any segment of the axial skeleton may be involved; however, the distribution of disc calcifications possesses a
Differential diagnosis The combination of disc space narrowing, discal calcification, band-like ossification of the intervertebral disc, and kyphosis at the thoracolumbar junction may resemble abnormalities in AS [9]. Confusion between these two diseases is further accentuated by abnormalities in the sacroiliac joints, symphysis pubis, and appendicular large joints [25]. Table 2 summarizes the main differences among ochronotic arthropathy, AS, and OA. Disc calcifications must be distinguished from those of the following: AS, diffuse idiopathic skeletal hyperostosis (DISH), juvenile idiopathic arthritis, calcium pyrophosphate dehydrate crystal deposition disease (CPPD), Klippel-Feil syndrome, and congenital and acquired fusions of the spine [9]. Additionally, disc space loss, vacuum phenomena, vertebral-body sclerosis, and variable osteophytosis resemble the changes of intervertebral osteochondrosis, a form of degenerative disease of the axial skeleton. However, the diagnosis of ochronosis must be considered for any patient with multilevel vertebral-body disc involvement. Lumbar disc herniation has also been observed in case studies as the presenting symptom of ochronosis; it is hypothesized that herniation
Clin Rheumatol Table 2 Differential diagnosis. Ochronotic arthropathy, ankylosing spondylitis, and osteoarthritis*
Distribution of abnormalities
Ochronosis
Ankylosing spondylitis
Osteoarthritis
Spine+++ Knees+++ Hips++ Shoulders+
Spine+++ Knees+ Hips+
Spine+++ Knees++ Hips++ Hands+++
Sparse Dense/water like Common Broad Mild
None Mild to moderate Rare Thin+vertical Severe
Prominent Mild to moderate Rare None Mild to severe
Symmetrical or asymmetrical Scanty Prominent
Symmetrical
Asymmetrical space narrowing Prominent Sparse
Axial abnormalities Osteophytes Discal calcification Multiple vacuum discs Syndesmophytes Apophyseal joint disease Peripheral joints Joint-space loss
*Modified from Reference 21
Osteophytes Intra-articular osseous bodies, fragmentation
occurs due to weakening of the fibrocartilage by ochronotic pigment deposition [26]. The intervertebral discs containing black material on discectomy may be the first datum leading to diagnosis.
Peripheral joint involvement Involvement of the large peripheral joints usually occurs about 10 years after spinal changes in alkaptonuria. Based on the analysis of 26 patients with ochronotic arthropathy, it may be noted that the small joints were spared and the large joints were predominantly affected in the following order: knees, 64 %; shoulders, 43 %; and hips, 35 % [27]. Overall, the radiographic changes in the diarthrodial joints are reminiscent of those observed in primary OA, including joint-space narrowing, bony sclerosis, and osteophytosis. Certain findings (Table 2) in ochronotic arthropathy allow its differentiation from other conditions as follows: 1. Unusual sites of joint involvement. Severe glenohumeral joint disease resembling OA in the absence of significant trauma suggests the diagnosis of ochronosis. Likewise, advanced changes in the sacroiliac joints and symphyseal joints (joint-space narrowing and calcification) [28] may be a clue to the presence of ochronotic joint involvement. Conversely, involvement of the elbows, wrists, and small joints of the hands were uncommonly recognized in this metabolic disorder [29]. 2. Joint-space loss with an unusual pattern. Symmetrical joint-space narrowing in the hips and shoulders, along with isolated lateral femorotibial loss of knee joint space, is unusual for OA and is observed in ochronosis.
None None
3. Unusual bony sclerosis, fragmentation, and intra-articular loose (osteochondral) bodies [9]. Deposits of HGA deteriorate the formation and architecture of proteoglycans in the hyaline cartilage, leading to fragmentation and rapid, destructive arthropathy [30]. The rapid disappearance of the femoral head was initially reported in two cases of ochronosis [31]. This report was followed by several reports on rapidly progressive arthropathy of the hip joint [32–34]. In undiagnosed cases, severe arthropathy leads to a variety of surgical procedures; macroscopic inspection of the joint during surgery shows darkening of the cartilage or a “black joint,” immediately evoking the diagnosis of ochronosis [35]. The production of multiple, loose osteochondral bodies (calcified and ossified pea-sized, or even larger, bodies of diverse shape) is a particular characteristic of ochronotic arthropathy and is a sign of ochronotic chondromatosis [36]. Synovial fluid analysis is reported as non-inflammatory in nature [37]; interestingly, the effusions are yellowish in color, and this remains unchanged even after prolonged standing in air, suggesting a low concentration of HGA [5]. Osteophyte formation is variable and may not be a prominent feature of this metabolic disorder. Humeral and femoral head avascular necrosis may occur in ochronosis [12].
MRI and nuclear medicine techniques Magnetic resonance imaging (MRI) findings mirror the characteristic radiographic changes of ochronosis; uniform loss of intervertebral disc height with central intradiscal low T1 and T2 signals, corresponding to intradiscal calcification and multilevel disc prolapse, is characteristic [38]. Diffuse type 2
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modic (fatty) endplate changes are unusual. Ochronotic spine should be considered in the differential diagnosis when these changes are present. Nuclear medicine techniques provide useful information that can be incorporated into the disease severity assessment. A semiquantitative isotope bone scan score has been proposed, depending on the involvement of large joints. This remains to be validated in a suitable cohort of patients [39]. Other imaging techniques, such as ultrasonography, may be useful for assessing degenerative changes. To date, only isolated case reports showing joint effusion, synovial proliferation, and increased vascularization have been reported [37]. Post-mortem examination of an unsuspected case of alkaptonuria revealed, in addition to ochronotic pigment, extensive CPPD deposits in tracheal, costal, femoral, and patellar cartilage tissues [40].
Treatment Several strategies have been used with little success. Physical therapy can be helpful in some cases. High doses of vitamin C and a low-protein diet have not proven effective. Pain control by means of paracetamol, anti-inflammatory drugs, opioids, anticonvulsants, local anesthetics, gabapentin, acupuncture, and nerve block has been attempted [8]. Nitisinone selectively inhibits the 4-hydroxyphenyl-pyruvic acid oxidase enzyme and reduces the formation of HGA, may prevent morbidity if started before symptomatic stage, or may slow progression in patients beginning with symptoms [8]. In a mouse model, nitisinone completely inhibited ochronosis; however, it caused increased blood tyrosine, whose clinical translation is unknown [41]. The ideal treatment would be replacing the missing enzyme either as an enzymatic protein or replacing the gene. We consider ochronotic arthropathy as a model of metabolic degenerative joint disease, with a rapidly progressive course that culminates in joint replacement, particularly of weight-bearing joints. Disclosures All authors declare no conflicts of interest. Ventura-Ríos L. None. Hernández-Díaz C. None. Gutiérrez-Pérez L. None. Bernal-González A. None. Pichardo-Bahena R. None. Cedeño-Garcidueñas A. None. Pineda C. None.
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