Rheumatology

Ochronosis

Does this patient have ochronosis?

Alkaptonuric ochronosis is the systemic manifestation of accumulated homogentisic acid due to a rare autosomal recessive disorder involving the metabolism of phenylalanine and tyrosine to fumarate and acetoacetate. The defect is a loss of function mutation mapped to chromosome 3q2, which results in the deficiency of the enzyme homogentisate 1,2-dioxygenase.

This leads to abnormal accumulation of the intermediate homogentisic acid in the body and increased urinary excretion of this product. The arthritis associated with this condition is called ochronosis due to the dark color of the pigment that is deposited in the cartilage that resembles the vegetable okra.

Initial symptoms

Initial symptoms, which can occur as early as infancy, include characteristic black discoloration of urine due to homogentisic acid oxidation that occurs after urine has been standing.

Systemic complications are often evident by the third to fourth decade of life, due to selective ochronotic pigment deposition in connective tissues. The tissue types that are commonly involved causing rheumatological disease include hyaline cartilege, tendons, ligaments and muscles.

Back pain

Back pain is often the first sign of systemic involvement. It is often described as a dull, aching pain with stiffness. It can occur as early as ages 20-30. Sudden, severe sharp pain can also be the initial symptom, although much less frequent, occurring from a ruptured nucleus pulposus.

Posture can be affected by deposition due to thoracic kyphosis. Loss of lumbar lordosis, decreased spinal mobility, and loss of overall height can occur. Cervical spine and pubic symphysis joints can also be affected. Sacroiliac and apophyseal joints are not affected.

Schober's test is often positive reflecting loss of lumbar mobility. Significant morning stiffness is not a component of the presentation. Chest expansion and respiratory function can become impaired. Osteoporosis and osteopenia is commonly found in this population, as well as fractures.

Ochronotic arthropathy

Ochronotic arthropathy is a manifestation of long-standing alkaptonuria. Sites of peripheral arthritis follow the back pain, and primarily include large joints, often sparing the small joints. Initial arthritic symptoms include pain, stiffness, and limited range of motion, favoring a flexed position. Symptoms may be acute, with joint effusions and synovitis or insidious, with pain on weight bearing.

Physical exam findings include crepitance, loss of range of motion, synovitis, and joint line tenderness. With minimal provocation, joint and bursal effusions, as well as ligament tears can occur.

Calcium pyrophosphate deposition disease

Calcium pyrophosphate deposition disease frequently co-exists with ochronotic arthritis.

Other sites of pigment deposition

Common nonarticular sites of deposition include: hyaline cartilage in the respiratory tract (including nasal, laryngeal, tracheal, and bronchial), endocardium of the heart, heart valves (base and anuli of the aortic and mitral valves), walls of arteries, sclera and skin.

Genitourinary obstruction can occur from ochronotic calculi in the kidney and prostatic calculi can develop. Early visual signs of disease include dark pigmentation of the ear pinna, helix, antihelix, concha and nasal ala as well as grey-brown sclera discoloration.

Differential diagnoses

Differential diagnoses include:

  • Extrinsic ochronosis, a non-inheritable disease process due to medications, most commonly with hydroxyquinone, and products containing resorcinol, phenol mercury and picric acid.

  • Osteoarthritis which can have similar physical exam findings, symptoms and radiographic changes.

  • Rheumatoid arthritis during acute presentations although small joints are often not affected.

  • Calcium pyrophosphate deposition disease and other crystalline disease can mimic ochronosis with periodic exacerbations.

  • Other secondary causes of osteoarthritis such as hemochromatosis.

  • Ankylosing spondylitis presents similarly with loss of spinal mobility, damage to spine and large joints but ochronosis differs by sparing the sacroiliac joint.

Imaging will help in the differentiation.

What tests to perform?

Clinical diagnosis is suggested by findings of early degenerative arthritis, abnormal pigmentation of the skin often involving the ear and urine that turns black on standing.

The first step in diagnosis is evaluating urinary homogentisic acid excretion (normal <0.01 mmol/mmol creatinine). This can be initially identified by urine organic acid analysis, by adding sodium hydroxide to a urine sample to facilitate oxidation. Diagnosis can be confirmed using mass spectrometry and/or gas chromatography for elevation in homogentisic acid > 100x normal in urine. Measurement and quantitation of homogentisic acid in plasma (undetectable in normal subjects), is another option, but standards of testing have not been established.

Genetic evaluation includes testing for the HGO mutation (on chromosome 3q) performed by polymerase chain reaction technique. GenBank accession number for HGO complementary DNA is AF045167 and protein sequence is AA02698.

Imaging

With the advance and frequency of MRI, CT and ultrasound, earlier presentations and increased diversity of involvement have been identified. MRI is recommended for early disease suspicious for tendonopathy, ligamentous tears and muscle involvement.

Spinal disease

Spinal radiograph is the gold standard for evaluation for back involvement. Calcification of multiple intervertebral disks is the hallmark finding in ochronosis. The disease often affects the lumbar spine initially. The earliest feature seen is vacuum disk phenomena with narrowing of the intervertebral disk space. Later changes include ossification of the disk, osteophytosis, loss of disk height with eventual collapse and fusion of adjacent vertebrae. Calcification of the intervertebral disk can help differentiate this from other forms of back disease.

Changes seen in ankylosing spondylosis such as calcification of the intervertebral ligaments, syndesmophytes, erosions and sacroiliitis do not occur.

MRI of the spine may reveal multiple levels of disk prolapse and a uniformly prominent low signal on T2 weighted imaging consistent with generalized disk desiccation.

Peripheral joint disease

Radiographs are the first step in evaluation of peripheral arthritis. The findings often resemble osteoarthritis. Findings include joint space narrowing and subchondral sclerosis. Notably, osteophytes are less commonly seen and this helps distinguish between osteoarthritis. Full-thickness erosions of articular cartilage to subchondral bone can occur in advanced cases. Involvement of the shoulders and hips are more severe, with osteochondral bodies seen.

The disease often spares the small joints radiographically, differentiating this from rheumatoid arthritis. Tendinous calcification and ossification may occur.

Bone health

Bone densitometry is recommended and special attention should be noted that lumbar calcification will falsely elevate bone mineral density. It may be beneficial to focus on density at the hip instead or to request additional bone densitometry of an extremity, such as the wrist.

Organ manifestations

Echocardiogram and cardiac CT/MRI further characterize valve defects and coronary calcification. Ultrasound is used for evaluating renal calculi and prostatic calcifications.

Biopsy

Biopsy is not necessary for diagnosis. In atypical cases arthroscopic findings consistent with the diagnosis include generalized synovial hypertrophy, brown-black discoloration of articular cartilage and menisci, and generalized cartilage degeneration. Samples should be sent for histological examination.

How should patients with ochronosis be managed?

Non-pharmacotherapeutic management

Management of ochronotic arthropathy is similar to that with osteoarthritis with the goal to reduce pain, maintain mobility and minimize disability. Begin with non-pharmacologic interventions that reduce the stress on the affected joints. This often requires physical, occupational and nutritional therapy. For interventions to improve body mechanics, weight-loss and avoidance of prolonged loading of the affected joint is recommended.

Orthopedic intervention is common, including arthroscopy for loose body removal and prosthetic joint replacements. Both indicated for advanced symptoms and often multiple joint replacements will be required. Both cemented and cementless implants are used. Tendon ruptures can be repaired.

Pharmacotherapeutic management

Pharmacological interventions include analgesics and NSAIDS. There currently is no medication that alters the progression of disease.

Osteoporosis and osteopenia are more prevalent in ochronosis compared to the general population and should be assessed frequently. Studies have shown this population to have higher rates of bone turnover. Treatment with bisphosphonates in limited trials has not proven effective. Evaluation and treatment for secondary causes should be pursued when applicable.

Treatment for decreasing the production of homogentisic acid is limited. Nitisinone, an inhibitor of 4-Hydroxyphenylpyruvic acid dioxygenase, the enzyme that converts 4-Hydroxyphnylpyruvic acid to homogentisic acid, has been shown to significantly decrease the urinary excretion of homogentisic acid. Studies confirming efficacy in ochronosis have not been positive as the side effects have precluded its use. Further evaluation is necessary regarding long term dosing, efficacy and side effects including ocular, dermatologic and neurological.

Dietary restrictions including low protein, phenylalanine and tyrosine have been studied but none have proven beneficial in reducing homogentisic acid production.

What happens to patients with ochronosis?

Epidemiology and pathophysiology

The incidence of alkaptonuria has been reported to be as common as 1:250,000 to 1:1,000,000 people, more common in areas of high consanguinity. The condition affects men and women equally. Life expectancy is normal but morbidity is significant. It has an autosomal recessive inheritance pattern mapped to chromosome 3q2. There is a large spectrum of HGO mutations identified that lead to disease development. Over 40 mutations have been found involving 106 of 114 alleles on this gene.

Alterations of the tyrosine degradation pathway, which ultimately includes the conversion of phenylalanine to succinylacetone, with the third intermediate being homogentisic acid (metabolized by kidney and liver), are responsible for ochronosis. The genetic mutations described above can result in a loss of function mutation with deficiency of homogentisate 1,2 dioxygenase stopping the degradation pathway, leading to abnormally elevated homogentisic acid in the body.

Theories on pathophysiology

It has not been elucidated by what exact mechanism the homogentisic acid elevation leads to pigment formation, tissue deposition and the subsequent disease ochronosis. Theories on the pathophysiology of joint disease include:

  1. Homogentisic acid is a chemical irritant or that it can alter structure and biochemical signaling.

  2. Homogentisic acid is oxidized to the byproduct benzoquinone acetate via homogentisic acid polyphenol oxidase. Benzoquinone acetate may form bonds to connective tissue altering the cross linking, thus creating tissue damage.

  3. Oxidation of homogentisic acid leads to free radical formation which can incite inflammation.

  4. Decreased activity of lysyl hydroxylase, a cartilage enzyme required for cross linking, has been observed but its role and mechanism are not known.

Additionally, it is known that accumulation of homogentisic acid is inversely related to renal function, and this is an exacerbating factor.

Deposition of pigment

Deposition of pigment into tissue causes arthropathy, primarily at the large joints including the knees, hips and shoulder. The small joints in affected individuals have pathological evidence of pigment deposition but clinical involvement at the hands, wrists or feet are less common. As deposition occurs at articular cartilage, it becomes weak, brittle and can break, fragment or rupture.

These pieces can then embed in synovium which incites a nonspecific inflammatory synovitis characterized by chronic inflammation, degeneration, and osteoarthritis. The "shards" are often visible on synovial samples and massive deposition results in black hypertrophic synovium. Articular cartilage at synovial joints including the hip and knee can become black and extremely brittle. Tendons and muscles will thicken, tear and rupture due to ochronotic pigment both deposited within the tissues and at adjacent structures.

Microscopically, the diagnostic feature of ochronosis in the synovium is the presence of "shards" of ochronotic cartilage. Under electron microscopy, this cartilage has membrane bound granules of electron dense ochronotic pigment in synovial lining cells and macrophages. Additional findings include fibrillation at the articular surface after pigment deposition.

Pigment has an affinity for fibrillary collagens that are surrounded by a mucopolysaccharides, as seen in hyaline cartilage of the joints. Pigment also deposits in areas of degenerated connective tissue. Lymphocytic infiltrates, synovial chondrometaplasia, hyperplasia of synovial lining cells, and synovial polyps can be seen.

Spine and bone damage

The spine is a common site of deposition causing spondyloarthropathy. Intervertebral disks will accumulate pigment and this will weaken the surrounding cartilage allowing for disk herniation. The annulus fibrosis and nucleus pulposus become ochronotic and the nucleus pulposus may ossify, or rupture. Vertebral osteophyte formation is common. The intervertebral disks will degenerate and ankylosis of adjacent vertebral bodies can occur. Loss of disk height is common.

Bone metabolism is altered in ochronosis and accelerated bone loss is seen. Urinary excretion of N-telopeptides of type 1 collagen, a biomarker of resorption, is commonly elevated. Additionally, the polymer formed from oxidized homogentisic acid may contribute to bone matrix damage, osteocyte viability and collagen crosslinking impairment.

Other significant issues

Cardiac involvement often occurs later, over the age of 50, with aortic and mitral valve deposits, causing aortic stenosis and coronary artery calcifications. Skin manifestations occur both in the dermis and sweat glands. The most common site of discoloration is the ear pinnae. Globally, the skin turns grey to slate blue in color, often more prominent in sun exposed areas and in regions where sweat glands are present. Ocular complications include pigment deposition in the outer structures of the eye including the sclera, cornea, conjunctiva, tarsal plates and eyelids. This does not lead to significant visual impairment.

Genitourinary tract can be affected with renal calculi, less frequent are urinary bladder calculi. Prostate deposition occurs with stone formation.

Long term disability from ochronosis primarily is due to cardiac and arthritic etiologies.

Pharmacologic considerations

Future research is needed in genetic therapy or exogenous therapy to replace the missing enzyme, homogentisic acid oxidase.

How to utilize team care?

Specialty consultations

Specialty consultations may include: orthopedic surgery for joint replacements, neurosurgery for disc disease and possible fusion, cardiology, genetics and genetic counseling, urology and ophthalmology

Therapists

Physical and occupational therapy for strengthening, balance, and activities of daily living support.

Are there clinical practice guidelines to inform decision making?

No.

What is the evidence?

Bayindir, P, Ovali, GY, Pabuscu, Y, Temiz, C, Duruoz, T. "Radiologic Features of Lumbar Spine in Ochronosis in Late Stages". Clin Rheumatol. vol. 25. 2006. pp. 588-590.

(A case report examining late lumbar spine findings on XRAY CT and MRI in patients with ochronosis.)

Phornphutkul, C, Introne, WJ, Perry, MB, Bernardinini, I, Murphey, MD, Fitzpatrick, DL. "Natural History of alkaptonuria". N Engl J Med. vol. 347. pp. 2111-21.

(Study of 58 patients with alkaptonuria evaluating organ and joint involvement, symptoms, and treatment. Additionally reviews the tyrosine degradation pathway and genetic basis of disease.)

Zatkova, A, Chmelikova, A, Polakova, H, Ferakova, E, Kadasi, L. "Rapid detection methods for five HGO gene mutations causing alkaptonuria". Clin Genet. vol. 63. pp. 145-9.

(A review on genetic testing methods and mutations in a high prevalence population.)

Aliberti, G, Pulignano, I, Schiappoli, A, Minisola, S, Romagoli, E, Proietta, M. "Bone metabolism in ochronotic patients". J Int Med. vol. 254. pp. 296-300.

Aliberti, G, Pulignano, I, Pisani, D, March, RM, Del Porto, F, Proietta, M. "Bisphosphonate treatment in ochronotic osteoporotic patients". Clin Rheumatol. vol. 26. 2007. pp. 729-735.

(Both explore the pathophysiology and barriers to bisphosphonate therapy in this population.)

Keller, J, Macaulay, W, Nercessian, O, Jaffi, I. "New developments in ochronosis: review of the literature". Rheumatol Int. vol. 25. 2005. pp. 81-85.

(An in depth review of genetics, pathophysiology, and treatment options.)

Gaines, J. "The Pathology of Alkaptonuric Ochronosis". Hum Pathol. vol. 20. 1989. pp. 40-6.

(An overview of pathological findings of all organs systems affected by ochronosis based on six cases.)

Jenkins, J. "Inborn Errors of Metabolism affecting connective tissue". Rheumatology Secrets. 2002. pp. 401-409.

(A concise review of the articular manifestations of ochronosis.)

Suwannarat, P, O'Brien, K, Perry, MB, Sebring, N, Bernardini, I, Kaiser-Kupfer, MI. "Use of nitisinone in patients with alkaptonuria". Metabolism Clinical and Experimental. vol. 54. pp. 719-728.

(A small open label study that evaluated the safety and efficacy of nitisinone over a 3-4 month period. It could be used as a basis for future studies as it showed improvement in urinary HGA levels and few side effects.)

O'Brien, WM. "Biochemical, pathologic and clinical aspects of alkaptonuria, ochronosis and ochronotic arthropathy". Am J Med.. vol. 34. 1963. pp. 813-9.

(One of the seminal papers on ochronosis, comparing 163 cases for joint involvement, symptom onset, physical exam and x-ray findings.)

Schumacher, RH, Holdsworth, DE. "Ochronotic Arthropathy. I. Clinicopathologic Studies". Seminars in Arthritis and Rheumatism. vol. vol. 6. 1977. pp. 207-245.

(A seminal paper reviewing the symptoms and pathology of seven cases.)
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