Alkaptonuria, Ochronosis, and Ochronotic Arthropathy

Alkaptonuria (also known as alcaptonuria) is an autosomal recessive condition caused by homogentisate 1,2-dioxygenase deficiency in the liver. The consequence of this deficiency is homogentisic aciduria (alkaptonuria), which is followed by ochronosis and ochronotic arthropathy.

Ochronosis

Ochronosis is caused by deposition of homogentisic acid as a polymer in collagenous tissues, resulting in a dark blue discoloration of sclera, cornea, cartilage, and heart valves. Ochronosis is seen on physical exam and on biopsy by noting the dark blue discoloration.

Not all cases of ochronosis are genetic. Exogenous ochronosis, which is clinically and histologically similar, is differentiated by its lack of systemic effects. It is most commonly caused by hydroquinone-containing products such as skin lightening creams, which paradoxically cause skin hyperpigmentation in these patients. Exogenous ochronosis can also occur following the use of antimalarial medications and products with resorcinol, phenol, mercury or picric acid.

Ochronotic Arthropathy

Longstanding ochronosis can lead to joint destruction. The mechanism is thought to be a positive feedback loop initiated by pigment deposition, which makes adjacent tissue susceptible to pigmentation and leads to progressive tissue destruction.

Ochronotic arthropathy can be seen on imaging as joint destruction and mineral deposition. Characteristic imaging findings of ochronotic arthropathy include involvement of the thoracic and lumbar spines with relative sparing of the cervical spine. In the thoracolumbar spine, one may see osteopenia, loss of lumbar lordosis, multilevel calcification of the annulus fibrosus, vacuum phenomenon, and progressive narrowing of intervertebral spaces. Patients with longstanding ochronosis can have severe kyphosis, obliteration of the intervertebral spaces, and marginal osteophytes that can look like syndesmophytes.

Findings in the appendicular skeleton are nonspecific and resemble osteoarthritis, except that there is less pronouced ostephyte formation than would be expected for the degree of joint space narrowing. Chondrocalcinosis can be seen. In the knee, which is typically involved, the lateral compartment is more severely affected.

Differential considerations for disk calcifications of ochronotic arthropathy include:

• Calcium pyrophosphate dihydrate deposition disease
• Degenerative or post-traumatic osteoarthritis
• Ankylosing spondylitis
• Hemochromatosis
• Hyperparathyroidism
• Acromegaly
• Amyloidosis

Differential considerations for chondrocalcinosis include:

• Calcium pyrophosphate dihydrate crystal deposition disease (CPPD)
• Degenerative or post-traumatic osteoarthritis
• Hemochromatosis
• Hyperparathyroidism
• Idiopathic

References

• Aquaron RR. Alkaptonuria in France: past experience and lessons for the future. J Inherit Metab Dis. 2011 Dec;34(6):1115-26.
• Baeva M, Bueno A, Dhimes P. AIRP best cases in radiologic-pathologic correlation: ochronosis. Radiographics. 2011 Jul-Aug;31(4):1163-7.
• Bongiorno MR, Aricò M. Exogenous ochronosis and striae atrophicae following the use of bleaching creams. Int J Dermatol. 2005 Feb;44(2):112-5.
• Taylor AM, Boyde A, Wilson PJ, Jarvis JC, Davidson JS, Hunt JA, Ranganath LR, Gallagher JA. The role of calcified cartilage and subchondral bone in the initiation and progression of ochronotic arthropathy in alkaptonuria. Arthritis Rheum. 2011 Dec;63(12):3887-96.