Abstract
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Alkaptonuria is an extremely rare disorder of tyrosine metabolism caused by an autosomal recessive enzymatic deficiency of homogentisic acid (HGA) oxidase, causing its accumulation in collagenous structures, especially in hyaline cartilage.
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It is characterized by a triad of homogentisic aciduria, bluish-black discoloration of connective tissues (ochronosis) and arthropathy of the spine and large weight-bearing joints.
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Several clinical manifestations were described including coronary and valvular calcification, aortic stenosis, limited chest expansion, and renal, urethral and prostate calculi as well as ocular and cutaneous pigmentation.
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Skeletal affection usually presents as spondylotic changes of the spine. The knee is the most common peripheral joint to be involved. Enthesopathy or tendon ruptures may occur, and reduced bone density is not unusual.
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A low-protein diet and ascorbic acid may reduce HGA levels. Nitisinone can safely and effectively reduce HGA production and urinary excretion.
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In severe ochronotic arthropathy, joint arthroplasty can offer reliable pain relief and excellent functional outcomes. Cementless fixation is successful in young patients.
Introduction
Alkaptonuria is an extremely rare autosomal recessive metabolic disease caused by deficiency of homogentisic acid (HGA) 1,2-dioxygenase, affecting one in 250,000–1,000,000 live births (1, 2, 3, 4, 5). This enzyme normally changes HGA to maleylacetoacetic acid, and its deficiency results in accumulation of HGA and its oxidized product, benzoquinone acetic acid, in collagenous structures and excessive renal excretion, causing urinary discoloration on standing or alkalinization, hence the name alkaptonuria (2, 6, 7). It is characterized by a triad of homogentisic aciduria, ochronosis and progressive degeneration of all affected structures with widespread joint arthritis (ochronotic arthropathy (OcA)) (4, 5).
Ochronosis is the deposition of bluish-black pigmented metabolic by-products that look microscopically ochre (yellow in Greek) in connective tissues, especially in hyaline cartilage (2, 8). In addition to ocular and cutaneous pigmentation, affected individuals can suffer a wide spectrum of manifestations (9). Cardiovascular involvement usually presents with coronary and valvular calcifications, sometimes with aortic stenosis (4, 10, 11). Stiffness of the costal cartilage can cause limited chest expansion with dyspnea (12). In the genitourinary tract, renal, urethral and prostate calculi are common (2, 4, 9). Systemic metabolic affection reduces bone density causing osteopenia and osteoporosis (7). Ochronotic tendinopathy usually affects large tendons (e.g. Achilles and patellar tendons), causing enthesopathy and sometimes spontaneous rupture (7).
OcA is the most common complication of alkaptonuria (4). It usually remains asymptomatic until the fourth decade of life because of reduced renal clearance of HGA with age (2, 7, 13). Thereafter, the condition progresses rapidly with joint pain, swelling, limited range of motion and stiffness causing disability and reduced quality of life in affected individuals (4, 6, 7, 13). OcA usually involves the cervical, thoracic and lumbosacral spine causing disk degeneration and spondylotic changes (7, 12). The knee is the most common peripheral joint to be affected (7, 14, 15, 16).
Historical review
The first verified case of ochronosis was described in an Egyptian mummy (Harwa) from 1500 B.C. (17). Scribonius in 1584 reported a boy who passed urine as black as ink (18). Boedeker in 1859 first used the term “Alcapton” to describe a second urinary reducing substance in a patient with glycosuria on account of its behavior with alkali (19). The substance was identified in January 1891 as 2,5-dihydroxyphenylacetic acid or HGA by Wolkow & Baumann (20). Virchow called the condition ochronosis (yellow disease) in October 1866 because the pigment accumulated looks yellow under microscopy (21). Albrecht (22) was the first to recognize that ochronosis and alkaptonuria represent different aspects of the same disease in 1902. In the same year, Garrod in London identified the hereditary nature of the disease (23). In June 1908, he described alkaptonuria in his Croonian lectures as the first inborn error of metabolism that obeys the Mendelian principles of autosomal recessive inheritance in humans (24). Neubauer (25) mapped the complete tyrosine-degradation pathway by 1909. Several years later, the specific hepatic enzyme defect in alkaptonuria was demonstrated to be HGA-oxidase deficiency, one of six enzymes required for the catabolism of the aromatic amino acids phenylalanine and tyrosine (26).
Etiopathology
Several mechanisms for the development of ochronotic arthritis have been described. Hamdi and coworkers proposed that benzoquinone acetic acid inhibits lysine hydroxylase enzyme and thereby reduces cross-linkage of collagen fibers (13). This enhances fiber vulnerability to stress and shearing injury causing connective tissue failure with cartilage fragmentation (13). Synovial adherence of these cartilage fragments may cause inflammation, fibrosis, loose body formation or chondromatosis (27). Taylor and coworkers attributed ochronotic arthritis to altered mechanical properties of the pigmented hyaline cartilage that becomes weak and brittle, loses elasticity and develops poor resistance to mechanical strain (8). Furthermore, it has been shown that HGA oxidation produces free oxygen radicals, which may induce inflammatory, degenerative and amyloidogenic changes (7, 28). On the cellular level, this oxidative stress was recently proved to affect human osteoblastic functionality and induce autophagy alterations leading to chondroptosis in human chondrocytes (29, 30). In addition, pigment deposits may initiate aggressive osteoclastic resorption underneath hyaline cartilage, causing complete loss of the subchondral plate (8). Ochronotic pigments deposited in bone impair mineralization of the newly formed osteoid matrix with decreased bone mineral density and an increased risk of fragility fractures (7).
Clinical presentation
Unlike rheumatoid arthritis, which affects the small joints of the hands and feet, OcA predominantly involves the spine and large weight-bearing joints and in contrast to ankylosing spondylitis, the sacroiliac joints are relatively spared and bamboo spine, annular ossification and syndesmophytes do not occur (7, 31). Patients with ochronotic spine disease typically present with back pain and stiffness, eventual loss of lordosis and exaggeration of thoracic kyphosis (7). Ochronotic spondylarthropathy is claimed to be more severe in HLA-B27-positive individuals (32). Radiologically, spine affection is associated with disk herniation, extensive multilevel calcification of ochronotic intervertebral disks and vacuum phenomena (7). Further degenerative changes may cause spinal stenosis with myelopathy. Affection of the large weight-bearing joints occurs several years after spinal involvement. The knee is the most commonly affected peripheral joint in up to 64% of cases (7). Upper limb involvement is extremely rare. The radiological features of peripheral joint involvement include severe degenerative changes with loss of joint space and subchondral bone sclerosis, with minimal or no osteophytic changes (in contrast to osteoarthritis). Aspiration of the synovial fluid often reveals floating black particles (ground pepper sign) (33). Coexistence of ochronosis and rheumatoid arthritis, ankylosing spondylitis or chondrocalcinosis has also been reported (4).
Treatment
Treatment options are limited in alkaptonuria (2). Conservative treatment aims at controlling and ameliorating symptoms (31). Protein restriction and ascorbic acid have been shown to reduce urinary HGA excretion with reversal of bone abnormalities (34). However, a low-protein diet is difficult to maintain in such a lifelong disease. Nitisinone (Orfadin®), a synthetic reversible inhibitor of 4-hydroxyphenylpyruvate dioxygenase, is now the first disease-modifying drug approved by the European Medicine Agency (EMA) in 2020 for adults with alkaptonuria. It was originally approved by the Food and Drug Administration (FDA) in 2002 for the treatment of patients with hereditary tyrosinemia type I (HT-1). Two multicenter international studies (SONIA 1 with 40 and SONIA 2 with 138 patients) proved that nitisinone causes a safe and effective reduction of urinary HGA excretion in patients with alkaptonuria up to 99.7% with significant clinical improvement (35, 36). Genovese et al. demonstrated that nitisinone induced changes in serological and urinary biomarkers of bone and cartilage remodeling (37). However, it has little effect on the increased serum amyloid A observed in alkaptonuria, which may cause secondary amyloidosis (38). In ochronotic arthritis, physiotherapy, pain control and nonsteroidal anti-inflammatory drugs can limit symptoms with no effect on disease progression (39). In end-stage cases of OcA, surgical intervention through total joint replacement represents the best treatment available (6, 31).
Authors’ own experience
A middle-aged female patient suffering from polyarticular ochronotic involvement was treated in 2016 at the age of 53 years with bilateral anatomic shaftless total shoulder arthroplasty (EclipseTM, Arthrex, USA). Four years later, she presented with severe right-sided hip pain with limited weight-bearing. Radiologic examination revealed advanced narrowing of the joint space, and a pelvic MRI showed osteonecrosis of the right femoral head with advanced hip arthritis (Figs 1 and 2). She was admitted to the hospital due to intractable pain not responding to conservative treatment and was treated in 2020 using cementless total hip replacement with a short-stem (ArtiQo GmbH, Germany) through a minimally invasive posterior approach. Intraoperatively, the deep black discoloration of the joint, femoral head and synovium with complete separation of the articular cartilage was obvious (Fig. 3). OcA was then confirmed by histopathologic examination (Fig. 4). After finishing her rehabilitation, the patient presented six weeks postoperatively with severe groin pain and an inability to walk on the left side with radiologically evident chondrolysis of the left hip. She was again treated using minimally invasive left-sided cementless short-stem total hip replacement (Fig. 5). The intraoperative picture was similar to that of the former operation. The postoperative phases of all surgeries were uneventful. No complications were encountered during any surgery. The patient was completely pain-free and able to walk on crutches on the first postoperative day. She received daily physical therapy, gait training and range of motion exercises for the hip joint. Hip adduction, high flexion and excessive rotation were avoided to prevent prosthetic dislocation. She continued ambulatory rehabilitation after discharge, which she tolerated quite well. Walking aids were used for just 3 weeks. At the latest follow-up visit two years after surgery, the patient had an excellent functional outcome with no pain, free range of motion, total independence in daily activities and no prosthetic loosening or subsidence. Back pain with advanced multisegmental spondylotic changes was, however evident (Fig. 6).
Preoperative X-rays showing arthritis of the right hip.
Citation: EFORT Open Reviews 10, 2; 10.1530/EOR-2023-0112
MRI image of bone and cartilage destruction of the right hip.
Citation: EFORT Open Reviews 10, 2; 10.1530/EOR-2023-0112
The resected femoral head showing deep black discoloration.
Citation: EFORT Open Reviews 10, 2; 10.1530/EOR-2023-0112
Gross and microscopic image of ochronotic arthropathy.
Citation: EFORT Open Reviews 10, 2; 10.1530/EOR-2023-0112
Pelvic view showing bilateral cementless total hip replacement with short stems.
Citation: EFORT Open Reviews 10, 2; 10.1530/EOR-2023-0112
Advanced multisegmental spondylotic changes of the spine.
Citation: EFORT Open Reviews 10, 2; 10.1530/EOR-2023-0112
Discussion
To date, only few reports have described joint arthroplasty in OcA (1, 2, 3, 4, 6, 15, 16, 31, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50). In the largest series of 10 patients (12 hips), Pachore et al. (6) achieved satisfactory functional results with total hip replacement in alkaptonuric hip arthritis after up to 24 years of follow-up. Ilyas et al. (2) reported a case of a 45-year-old man with bilateral total hip and knee replacement because of advanced ochronotic arthritis, with no complications after 12 years. Di Marco et al. (40) and Araki et al. (41) reported similar good results after 6–7 years following bilateral total hip and knee arthroplasty for ochronotic arthritis. Demir (42) also reported on a case of alkaptonuric ochronosis with multiple joint replacements. Ye and colleagues (31) reported on bilateral total hip and right total knee arthroplasties in a patient with alkaptonuric arthritis. Fischer & Davis (4) reported on a patient who needed total joint replacement of her both knees and the right hip joint for OcA. In addition, da Silva Martins Ferreira et al. (43) reported on a male patient suffering from alkaptonuria since the age of 40, undergoing total replacement of his left hip and both knees done after the age of 60 years. Fernando et al. (1) presented a case of bilateral OcA of the hip that was successfully managed by staged bilateral total hip replacement. Saini et al. (15) presented a female patient with bilateral total knee arthroplasty due to OcA. Lee et al. (16) also described a case of bilateral knee arthroplasty in a male patient with ochronotic arthritis. Aydoğdu et al. (44) reported a case of OcA treated using cementless knee arthroplasty with a 4-year follow-up. Ozmanevra et al. (45) also described satisfactory results two years after simultaneous bilateral cemented knee arthroplasty in a 69-year-old male patient with ochronosis. Sahoo et al. (46) reported on a 51-year-old male patient with bilateral knee replacement because of severe tricompartmental osteoarthritis with varus deformities and limited range of motion. Drakoulakis et al. (47) reported significant improvement of shoulder function after bilateral total shoulder arthroplasty in a 53-year-old man with OcA. Acar et al. (3) also treated a female patient with hip and knee arthroplasty due to OcA. Mazoochy and Razi (48) reported on knee and hip joint replacement in a patient with OcA. Harun et al. (49) also reported on knee and hip replacement in a 60-year-old female ochronotic patient with black joints. Cebesoy et al. (50) treated a 46-year-old male patient with ochronosis using cementless total hip arthroplasty of the right hip due to osteoarthritis (Table 1).
Case reports on total joint arthroplasty in ochronotic arthropathy.
Case reports | Patients, n | Age, years | Sex | Joints | FU, years |
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Authors’ case 2024 | 1 | 53 | Female | Both hips and shoulders | 2 |
Pachore et al. (6) | 10 | 53–80 (63) | 6 males; 4 females | 12 hips | 3–24 (16.7) |
Ilyas et al. (2) | 1 | 45 | Male | Both hips and knees | 12 |
Di Marco et al. (40) | 1 | 50 | Female | Both hips and knees | 7 |
Araki et al. (41) | 1 | 56 | Male | Both hips and knees | 6 |
Demir (42) | 1 | 70 | Male | Both hips and knees | 14 |
Ye et al. (31) | 1 | 64 | Female | Both hips and right knee | 3 |
Fischer & Davis (4) | 1 | 69 | Female | Both knees and right hip | 5–7 |
da Silva et al. (43) | 1 | 67 | Male | Left hip and both knees | 0.5–5 |
Fernando et al. (1) | 1 | 69 | Female | Both hips | 1.5 |
Saini et al. (15) | 1 | 52 | Female | Both knees | 2 |
Lee et al. (16) | 1 | 54 | Male | Both knees | 2 |
Aydoğdu et al. (44) | 1 | 48 | Male | Both knees | 4 |
Ozmanevra et al. (45) | 1 | 69 | Male | Both knees | 2 |
Sahoo et al. (46) | 1 | 51 | Male | Both knees | 2.3 |
Drakoulakis et al. (47) | 1 | 53 | Male | Both shoulders | 3 |
Acar et al. (3) | 1 | 62 | Female | Left hip and right knee | 1.5 |
Mazoochy & Razi (48) | 1 | 57 | Female | Right hip and right knee | 2 |
Harun et al. (49) | 1 | 60 | Female | Right hip and left knee | Unknown |
Cebesoy et al. (50) | 1 | 46 | Male | Right hip | 0.5 |
FU, follow-up.
The above-mentioned own case confirms the excellent outcomes of cementless arthroplasty in OcA. The presented patient underwent bilateral total shoulder and hip replacements with an excellent functional outcome with full mobility and no pain or complications after two years of the last surgery. This compares favorably to former case reports that showed excellent short-term results in patients with OcA treated with joint arthroplasty. Pachore et al. suggested a total synovectomy, which we also did in our procedures (6). Total resection of the joint capsule, as recommended by Cebesoy et al., was, however, avoided due to stability issues with the posterior hip approach we used (50). Difficulties in achieving primary stability of the cementless implants were not encountered despite reduced quality of the affected bone, and no subsidence of the short stems was observed. This compares favorably to the long-term results reported by Ilyas et al. and Pachore et al. with cementless total hip replacement (2, 6).
Conclusion
In conclusion, alkaptonuric ochronosis is an ultra-rare, disabling, autosomal recessive metabolic disease causing severe polyarticular arthropathy with cartilage and bone destruction in relatively young patients. Total joint replacement with bone-sparing cementless implants can yield consistent pain relief and satisfactory functional recovery in patients with end-stage OcA.
ICMJE Statement of Interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the work reported.
Funding Statement
This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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