Keywords
black colored - ligamentum flavum - alkaptonuria
Introduction
Ochronosis is a syndrome caused by the accumulation of homogentisic acid (HGA) in
connective tissues. The phenomenon was first described by Rudolf Virchow in 1865.
Defective production of homogentisate 1,2-dioxygenase results in the accumulation
of HGA, a tyrosine degradation product, in the bloodstream. This enzyme deficiency
causes homogentisate polymers to accumulate and results in urine darkening, brown
black pigmentation of connective tissue, articular cartilage pathology, osteoporosis,
and pathomorphological changes in internal organs. Spinal involvement in alkaptonuria
is common, with the lumbar spine the most typical site in the form of early degenerative
changes with disk space involvement.[1]
Reddy et al first reported ligamentum flavum hypertrophy with an ochronotic deposit.[2] This report will be the second one on the subject. We present the clinical, radiologic,
and histologic manifestations of an ochronosis case with a brief review of the literature.
Case Report
A 71-year-old male patient was admitted with a complaint of low back pain for 8 years
with progressively worsening neurogenic claudication in the last 2 years. Neurologic
examination revealed a positive straight leg raise test at 30 degrees. No past history
of bowel and bladder disturbances or of surgery or trauma to the spine were reported.
Routine laboratory examination of the patient was normal. He had no family history
of metabolic abnormalities. Lumbar computed tomography showed calcifications of the
lumbar vertebrae, especially L3–L4–L5 vertebra, with narrowed intervertebral disk
spaces, intervertebral foramens, and vertebral canal ([Fig. 1a], [b]). Magnetic resonance imaging showed lumbar L3–L4, L4–L5 lateral recess stenosis,
foraminal stenosis, and narrowed intervertebral disk spaces ([Fig. 2a], [b]).
Fig. 1 (a, b) Lumbar computed tomography showing calcifications of the lumbar vertebrae, especially
L3, L4, and L5, with narrowed intervertebral disk spaces, intervertebral foramina,
and vertebral canal.
Fig. 2 (a, b) Magnetic resonance imaging showing lumbar L3–L4, L4–L5 lateral recess stenosis,
foraminal stenosis, and narrowed intervertebral disk spaces.
The patient was operated on under general anesthesia. He underwent decompressive laminectomy
for management of focal canal stenosis and foraminotomy at L3–L4 and L4–L5. The ligamentum
flavum was degenerated and black in color ([Fig. 3a], [b]). During the operation, in addition to the calcified and thickened ligamentum flavum,
we also observed that the dura mater was degenerated and thinned. There was no complaint
of pain or any neurologic deficits after the operation.
Fig. 3 (a, b) Intraoperative excised black-colored ligamentum pieces. (c–e) Histologic examination under light microscopy showing pigmentation and degeneration
of the ligamentum flavum tissue.
Histologic examination under light microscopy showed pigmentation and degeneration
of the ligamentum flavum tissue ([Fig. 3c–e]). After the histologic diagnosis, the patient was reexamined, and black ochronotic
pigmentation of the sclera, cornea, and skin was found ([Fig. 4a], [b]). On examination of the urine, a high level of HGA was found, and the patient was
diagnosed with alkaptonuria. The patient was informed that data concerning his case
would be submitted for publication.
Fig. 4 (a, b) Patient's sclera and ear showing black ochronotic pigmentation.
Discussion
Alkaptonuria is the result of loss of function, missense mutations of the gene on
chromosome 3q that codes for homogentisate 1, 2 dioxygenase (HGA). Scribonius first
described the urinary manifestations of the disease in 1584, and Boedeker in 1858
recognized the presence in urine of a reducing substance (alkapton) with an affinity
for oxygen in an alkaline medium.[2] Large quantities of HGA are excreted daily in the urine, where it oxidizes to benzoquinones,
which in turn form the melanin-like polymers that cause the discoloration of urine.
Accumulation of HGA and its metabolites in tissues causes ochronosis.[1]
[2]
The embedded pigments also form cross-linkages with pigment deposition in adjacent
fibers, stabilizing and reducing the elastic recoil of the fibers. This results in
hardening of elastic structures, increasing their rigidity and brittleness. Once ruptured,
the exposed pigments cause a foreign body reaction and inflammation. This pigment
deposition also invokes deposition of hydroxyapatite, the mineral responsible for
bone calcification, further hardening the connective tissue. The condition is most
often associated with alkaptonuria but can occur from exogenous administration of
phenol complexes like hydroquinone.[3]
[4] The pathogenesis of alkaptonuria includes chronic inflammation, degeneration, and
eventually osteoarthritis.
Characteristic radiographic findings of ochronotic arthropathy in the spine include
vertebral osteopenia, loss of normal lumbar lordosis, widespread disk calcification,
vacuum disk phenomenon, and progressive narrowing of intervertebral spaces. The thoracic
and lumbar spinal segments are involved first; cervical spine involvement tends to
occur later. Disk calcification occurs primarily in the annulus fibrosus and is thought
to be due to dystrophic calcification of the abnormal connective tissue.[5] The axial loading of body weight is maximal at the lower lumbar spine, which is
why it undergoes early and accelerated age-related degenerative changes. This disrupts
the integrity of the spinal stabilizing systems: passive (disk, ligament, bone, and
passive muscle), active (tendons and active muscle), and neural (the nervous system
and neural components within the passive and active structures), causing a transfer
in unfavorable loads onto other spinal structures.[6] The ochronotic deposits accelerate further calcium deposition in the ligaments and
enhances their stiffness.[2]
Patients with mild alkaptonuria may remain asymptomatic and the condition unrecognized
throughout life, like our patient. However, more commonly patients are recognized
in the 4th or 5th decade.[7]
[8] This case is also unusual because the patient's presentation was very mild. Patients
usually begin complaining of progressive low back pain in their 30s, and many patients
require joint replacement by 50 years of age. Our patient began to have back pain
in his 60s.
The diagnosis of alkaptonuria is usually based on the detection of degenerative joint
disease, ochronosis of the connective tissue, and darkening of urine after alkalization.
Clinical findings include pigmentation of the ear cartilage and the sclera of the
eyes that occurs after 30 years of age and vary in appearance. Almost all patients
experience arthritis of the knee and hip, and occasionally the shoulder. Retrospective
examination of our patient revealed only pigmentation of ear cartilage. Confirmatory
tests for diagnosis are chromatographic, enzymatic, or spectrophotometric determinations
of HGA.
Conclusion
In all the published case reports of lumbar and dorsal disk prolapse in ochronotic
patients, ours was the second one after Reddy et al described the first case of ligamentum
flavum hypertrophy with ochronosis.[2] Our patient with this metabolic disease had very thin dura mater, which might have
been unique to our case. We suggest that ochronotic patients may have more spinal
pathologies, and these patients and their complaints of pain should be considered
more carefully with respect to their metabolic pathology.
