Osteoarticular changes in Wilson's disease.

Osteoarticular Changes in Wilson’s Disease
Edward R. Feller and H. Ralph Schumacher
The musculoskeletal system of 17 patients with known Wilson’s disease
was studied clinically and radiographically. Major abnormalities were seen
only in 5 patients over 21 years of age. Multiple calcified loose bodies at
the wrists were present in 4, premature degenerative arthritis at the knees
with chondromalacia patellae in 4 and chondrocalcinosis at the knees in
2. Mild demineralizationwas seen at all ages and was present in 9 patients.
These unusual wrist and knee changes are infrequently recognized manifestations of Wilson’s disease in the adult.
Wilson’s disease (hepatolenticular degeneration) is an uncommon, recessively inherited disease characterized by excessive retention of copper with degenerative changes in
the brain, particularly the basal ganglia and
cirrhosis of the liver. T h e brown or greenishbrown Kayser-Fleischer rings at the limbus of
the cornea are pathognomonic of the disease.
T h e onset of clinical illness usually is during
childhood or adolescence (1). Presenting manifestations rarely may include renal tubular
disease, psychiatric disturbances or hemolytic
anemia (2).
Radiographic evidence of osteoarticular
changes has also been described, but most reviews of Wilson’s disease give little mention of
bone or joint disease (1-3). Some patients have
definite rickets (4,5 ) or osteomalacia (6) which
has occasionally been attributed to renal tubu-
lar dysfunction (6,7). Other changes, described
mainly in the radiologic literature, include
scattered subchondral bone fragmentation (6, 8-1 0), osteoarthritis (6-8), osteochondritis dissecans (2, 4, 8, 9), osteochondritis of
the spine (8), paraarticular calcifications (lo),
subchondral cysts (9), Milkman pseudofractures (6), pathologic fractures (6-9, 1 l ) , and
possible chondrocalcinosis (1 1). Demineralization has been reported in as many as 33 of 38
patients in one study (9).
This report describes a clinical and radiographic study of 17 patients with Wilson’s
disease. O u r results suggest that bony fragmentation or ossicles at the wrists, premature
degenerative arthritis particularly with chondromalacia patellae, and chondrocalcinosis,
may be characteristic findings in adults surviving with Wilson’s disease.
From the Arthritis Section, Department of Medicine,
Hospital of the University of Pennsylvania and Veterans
Administration Hospital, Philadelphia, Pa.
H . RALPH SCHUMACHER, MD: Assistant Professor of
Medicine and Director, Arthritis Research, University of
Pennsylvania School of Medicine, Chief, Arthritis Section,
VA Hospital, Philadelphia, Pa; EDWARD FELLER: Medical
Student, University of Pijon, Dijon, France.
Reprint requests should be addressed to: Dr. Schumacher, 206 Maloney Building, Hospital of the University of
Pennsylvania, 36th and Spruce Streets, Philadelphia, Pa
19104.
Submitted for publication Sept 20, 1971; accepted Jan
26,1912.
MATERIALS AND METHODS
Seventeen patients with known Wilson’s disease were
studied by clinical and radiographic examination of the
musculoskeletal system. Five were asymptomatic siblings of
patients with overt Wilson’s disease. In all 17, serum ceruloplasmin was less than 20mg/100ml (normal: 20 to 40
mg/100ml) and hepatic copper exceeded 200rg/g of dry
liver (normal: less than 50&g of dry liver) (12). Calcium,
phosphorous and alkaline phosphatase determinations were
obtained from hospital records or repeated at the time of
study. Urinary amino acids were measured in 12 patients.
A Parker-Pearson needle synovial biopsy of a knee joint
Arthritis and Rheumatism, Vol. 15, No. 3 (MayJune 1972)
259
FELLER
AND SCHUMACHER
Fig 1. Bone fragments or accesory bones
in the region of the radial-ulnar articulation
in this 26-year-old woman with neurologic
and hepatic symptoms for 11 years who had
been treated with penicillamine for 4 years
(Case 14). The left wrist showed similar
changes.
was performed on 1 patient (Case 10) and examined by
light microscopy, using hematoxylin and eosin and the
rubeanic acid stain for copper, and by electron microscopy.
Radiographic abnormalities were summarized and correlated with clinical assessment of hepatic, renal and central
nervous system disease.
RESULTS
Clinical Aspects
Four patients had
signs Or symptoms
of osteoarthropathy. A 31-year-old woman
Fig 2. Wrist showing several distinct bony ossicles
adjacent to the medial aspect of the distal radius with
a smaller less-defined density
at the radial-navicular joint.
There are also small cysts
in the distal ulna (anow).
Thirty-one-year-old woman
with hepatic and neurologic
symptoms for 20 years who
had been treated with penicillarnine for 11 years (Case
16).
260
Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972)
WILSON'S DISEASE
Fig 3. Small loose fragment adjacent to the
distal ulna in a 21-year-old woman with hepatic and neurologic abnormalities for l l
years and who had been treated with penicillamine for 6 years (Case 13).
(Case 16), presented with a history Of sporadic
pain and swelling of the knees for several years.
Sharp, diffuse pain was elicited by movement of
the left patella and knee joint. There was some
retropatellar crepitus in the left knee. A 26year-old woman (Case 14) had rough, painless
crepitus of the right wrist on flexion and extension. Retropatellar crepitus was present bilaterally. There was clicking at the lateral menis-
Fig4. Small calcified fragment at the base of the
middle phalanx of the long finger of the left hand.
A similar fragment was also seen about the radius
in the left wrist. Thirty-five-year-old man with neurologic and hepatic symptoms for 11 years treated
with penicillamine for 7 years (Case 17).
cus of the right knee on the McMurray test. A
10" flexion deformity was present at both knees.
A 29-year-old woman (Case 15) complained of
swelling of the knees with pain on walking for 3
Fig 5A (left). Irregularity of the posterior surface of the patella compatible with chondromalacia patellae. The articular surface of the femoral condyle is also irregular. Note the spurring on
the posterior surface of the patella. There are illdefined calcified densities near the tibiofibular
joint. Same patient as in Figure 2. B (right). Chondromalacia patellae in a 29-year-old woman
who had hepatic and neurologic symptoms for 12 years and who was treated with penicillamine
for 5 years (Case 15).
Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972)
261
FELLER AND SCHUMACHER
months. She had mild crepitus but no swelling
when examined.
A fourth patient, a 19-year-old boy (Case 10)
presented a 10-day history of dull, steady pain
and nontender swelling of the right knee. T h e
proximal interphalangeal joints were slightly
enlarged and firm. X-rays of the hands and
knees were normal in this patient. Joint aspiration and needle synovial biopsy of the right knee
were performed. Synovial fluid was viscous
with few cells and no crystals. T h e synovium
was negative for copper by the rubeanic acid
stain. There was only equivocal focal lining cell
proliferation and subsynovial fibrosis. Sedimentation rate, latex fixation test for rheumatoid factor, and antinuclear factor were done on
this patient only and were all normal or negative. Pain and swelling did not recur after the
aspiration. He was asymptomatic 1 year later.
X-ray Findings
The first 3 symptomatic patients and 2 others
over age 21 without symptoms or abnormal
physical findings had joint x-ray changes. All 4
21-year-old or older patients for whom bone
surveys of the wrists were available showed
multiple ossified or calcified loose bodies in or
about the wrist joints (Figures 1-4) and, in 1
patient each, at the hands and at the knees.
These apparent bony fragmentations were not
associated with osteoarthritic changes-ie, the
joint space was not narrowed nor was there
major subchondral sclerosis or irregularity.
Four patients (Table) showed premature osteoarthritic changes about the knees with hypertrophic spurring. In each case, this included
bilateral chondromalacia patellae (Figures 5A
and B). Two of these patients had linear densities in the ,joint space compatible with chondrocalcinosis (Figure 6).
Mild demineralization characterized by cortical thinning and prominence of the trabecular
pattern was seen in 9 patients. Four young
subjects had demineralization of long bones or
spine. Two other children had slight periarticular demineralization as did 3 older patients
with arthropathy. All demineralization was
mild and no compression fractures were seen.
Other less frequent skeletal changes are de-
Fig 6. Degenerative changes
at the knee with hypertrophic
spurring and mild localized demineralization involving the
medial femoral condyle and upper tibia. There is a linear density in the medial joint space
(arrow) compatible with chondrocalcinosis. Another irregular
density is seen in the lateral
joint space. Same patient as in
Figure 2.
262
Arthritis and Rheumatism, Vol. 15, No. 3 (MayJune 1972)
N
N
-5
a
m
E
z
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11
29F
31F
35M
15
16
17
~
7
12
20
26F
14
4
6
+
+++
++
+
0
++
+++
++
++
+++
+++
0
+++
0
0
0
0
+
Hepatic$
++
+
+
+
++
+++
0
+++
++
+
++
0
0
0
0
0
0
CNSS
+
+
+
+
0
0
+
0
+
+
+
0
+
+
0
0
0
0
Demineralization
++
Wrists,
hands
Wrists
*
Wrists,
knee
0
Wrists
*
0
0
0
0
0
0
0
0
0
0
++
++
++
-+
0
0
0
0
0
0
0
0
0
0
0
0
0
arthritis
of knee with
Articular chondrocalcified malacia
bodies
patellae
Osteo-
++
Subchondral cysts (ulna)
chondrocalcinosis (knee)
Subchondral cysts
(carpal)
Osteochondritis
(spine): scoliosis
Chondrocalcinosis
(knee)
Subchondral cysts
(hip)
Periosteal proliferation (femur)
Benign cortical
defect (femur)
Retarded skeletal
maturation
Other changes
Radiographic manifestations
+++
"Wrist, hand x-rays not available
+ = hepatic failure
+Hepatic criteria: 0 = absent: + = abnormal liver function tests: + = cirrhosis:
= minor changes (dysarthria. mild tremor):
= intermediate changes:
SCNS (central nervous system) criteria: 0 = absent:
= disabling rigidity with or without tremor
~~
5
11
11
19M
21F
12
13
3
2
3
7
12
19M
19M
10
11
7
11
1
4
-
1
5
1
2
2
2
2
2
6
2
-
-
-
-
15M
18M
18M
9M
12M
5M
8F
9F
9M
Age,
sex
8
9
7
5
6
1
2
3
4
Case
No.
of
Duration
Peniof
cillamine
symptoms therapy*
(Yr)
(yr)
Duration
Clinical manifestations
Table 1.RadiographicAbnormalities of Bones and Joints Related
to Clinical Manifestations of Wilson's Disease
m
UJ
F
9
B
0
FELLER AND SCHUMACHER
scribed in Table 1. Osteochondritis dissecans,
Milkman pseudofractures or pathologic fractures were not encountered. Four of the children had prominent growth recovery lines of
doubtful significance.
Results of all serum calcium, phosphorous
and alkaline phosphatase determinations were
within normal range. Renal tubular dysfunction manifested by mild aminoaciduria was
present in 3 children, 1 of whom had mild demineralization.
DISCUSSION
T h e calcified or ossified bodies at the wrists
of 4 of our adult patients are similar to changes
described by others as part of a process of bone
fragmentation (6, 8-10) or osteoarthritis (6-8).
These interpretations suggest that we are dealing with a predominantly noninflammatory
destructive and degenerative process. T h i s
would seem to be a good possibility in light of
other degenerative changes in cartilage seen
elsewhere, but we were unable to conclusively
visualize irregularities of articular cortex characteristic of fragmentation at the wrist. Mindelzun et al(9) reported subchondral cysts in 9
patients. Similar bone cysts in 3 of our patients
were often near the loose bodies but not clearly
enough related to be certain of an association.
Thus, it remains conceivable that the calcified
bodies might also represent accessory skeletal
elements or calcifications of bursae or tendons (1 3). Whatever their explanation, their
uniform presence in the adults studied and their
rarity in others in this age group suggests some
relationship to their Wilson’s disease.
Chondromalacia patellae has not been previously described in association with Wilson’s
disease but this was an unusually prominent
aspect of the premature degenerative arthritis
seen in several knees in our series. Boudin and
others (11) reported a case of possible chondrocalcinosis in the shoulder and knee joints of
one of their patients. Our finding of 2 cases
compatible with chondrocalcinosis at the knee
264
joint in patients with Wilson’s disease suggests
a similarity with the arthropathy of other
metabolic diseases, such as hemochromatosis (14, 15), hyperparathyroidism ( 1 6 ) , a n d
ochronosis (17) in which chondrocalcinosis can
also be seen. We have not yet been able to obtain cartilage biopsies or crystals from the synovial fluid to determine the type of calcium
crystal in any patients with Wilson’s disease.
Symptoms when present seemed most consistent with mechanical or degenerative type
disease. There was never morning stiffness or
clinical evidence of inflammation. T h e effusion
in the 19-year-old boy (Case 10) was noninflammatory. This patient has remained well
since the joint aspiration, so whether his effusion was related to the degenerative disease seen
in older patients is not yet known. Symptoms
when mentioned in other series have also been
predominantly mild arthralgias.
Radiographic evaluation of demineralization
is difficult, and, of necessity, approximate. We
made no systematic attempt to measure bone
density because films were taken at a variety of
hospitals with varying views and technics. None
of our patients developed the severe rickets or
osteomalacia seen by others (4-6). The most
severe changes have been described from India (5) and China (7) so that nutritional factors
may have also contributed. Our findings support the previous statements that many patients
with Wilson’s disease have apparent skeletal
demineralization, but this appears to be of
minor clinical importance. In one series of 9
patients no evidence of either osteomalacia or
osteoporosis (1 8) was reported. Quantitative
study of bone density should be of interest.
T h e mechanism of most osteoarticular
changes in Wilson’s disease is not clear. Shortterm experimental copper loading has not been
shown to produce bone or joint changes (19),
but copper-deficient dogs do develop skeletal
malformations (20). Some patients with Wilson’s disease and renal tubular dysfunction
develop rickets and osteomalacia (6); however,
most of our patients did not have demonstrable
Arthritis and Rheumatism, Vol. 15, No. 3 (May-June 1972)
WILSON’S DISEASE
renal tubular abnormalities. In 3 patients with
aminoaciduria, only 1 had mild demineralization. Finby and Bearn (6) noted that, because of
their tremor and spasticity, patients with Wilson’s disease are more susceptible to minor injuries than normal persons. Thus, chronic
tr a uma could be responsible for cartilage
damage and bone fragmentation. However,
these authors point out that osteoarthritic
changes have not been seen in patients with
other tremulous neurologic diseases, such as
Parkinson’s disease or multiple sclerosis. A recent report has implicated dyskinesias in the
production of cervical spondylosis (21), and
Rosenoer and Michell reported severe cervical
spondylosis in 1 patient with Wilson’s disease
marked by tremor (8). In our series, major bone
or joint changes occurred in patients with minimal neurologic involvement, while several patients with severe neurologic illness had little or
no evidence of bone or joint disease.
Some patients with cirrhosis of the liver have
osteoporosis and pseudocysts associated with
hepatic dysfunction (22), but again in our series
there was no correlation between osteoarticular
changes and severity of liver involvement.
Harpey et a1 (23) have reported a lupus-like
syndrome possibly induced by a penicillamine.
We saw no evidence of any similar reactions.
Although the degenerative joint involvement
in Wilson’s disease seems generally milder, an
analogy is possible with that of hemochromatosis. The prominent metacarpal phalangeal
and hip involvement seen in hemochromatosis
was not seen in our patients with Wilson’s
disease although involvement of these joints
has occasionally been described. T h e calcified
bodies and chondromalacia patellae seen in our
patients with Wilson’s disease have not been
characteristic of hemochromatosis. Despite
these differences in sites involved, the process
seems to be degenerative in both. In both
diseases, the metal excess is a possible mechanism for direct or indirect production of the
arthropathy. In vitro inhibition of pyrophosphatase by cupric and ferrous ions has been
shown. This has been suggested as a possible
mechanism allowing deposition of calcium pyrophosphate producing chondrocalcinosis in
Wilson’s disease and hemochromatosis (24).
In our series, younger patients showed only
occasional demineralization. The more severe
bone and joint lesions were present only in
older patients. No direct relation between total
disease severity, spasticity and tremors, liver or
renal disease and the production of osteoarthropathy has been established. Acute o r
chronic trauma was not considered a factor in
any case. All our patients with major bone and
joint disease had been observed at least 4 years
with symptomatic Wilson’s disease before penicillamine therapy was started. Since early reports of osteoarthritis and bone fragmentation
were before the advent of penicillamine therapy, it is unlikely that penicillamine causes these
osteoarticular changes. Whether earlier detection and treatment will prevent or minimize
bone and joint damage remains to be determined.
ACKNOWLEDGMENTS
The authors gratefully acknowledge the assistance of
Drs. Wallace Miller and John Kirkpatrick in the interpretation of the x-rays. We also thank Drs. Geraldine King,
John Bryfogle, Philip Holtzapple, and Warren Grover for
permission to study their patients.
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