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Hereditary chondrocalcinosis in a mexican-american family.

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1387
HEREDITARY CHONDROCALCINOSIS IN A
MEXICAN-AMERICAN FAMILY
BRUCE C. RICHARDSON, NEIL I. CHAFETZ, LINDA D. FERRELL,
JULIAN I. ZULMAN, and HARRY K . GENANT
In a study of 45 adults in a family of MexicanIndian ancestry, it was found that 22 (49%) had joint
symptoms resembling those of degenerative joint disease. Eleven family members had radiographic evidence
of chondrocalcinosis, and 1 adult and 3 adolescents had
clinical histories and examinations consistent with the
familial arthropathy, but no radiographic evidence of
disease. The cause of the arthritis in the affected family
members is calcium pyrophosphate crystal deposition.
The mode of inheritance appears to be autosomal dominant with a high degree of penetrance. The disease is
characterized by onset in the second to fifth decades of
either episodes of acute inflammatory arthritis or degenerative joint disease. A unique finding of this study was
a “halo” surrounding chondrocytes in 1 patient’s cartilage, demonstrating loss of the proteoglycans.
Hereditary chondrocalcinosis has been described in families from Canada ( I ) , Czechoslovakia
(2), Holland (3), Spain (4), Chile (5). France (6), and
Sweden (7). Three clinical forms have been noted. The
first, characterized by early onset and a relapsing mild
From the University of California, San Francisco.
Bruce C. Richardson, MD, PhD: Rheumatology Fellow,
University of California, San Francisco: Neil I. Chafetz. MD:
Assistant Professor of Radiology, University of California, San
Francisco; Linda D. Ferrell, MD: Assistant Professor of Anatomic
Pathology, University of California, San Francisco; Julian I . Zulman, MD: Assistant Clinical Professor of Medicine, University of
California, San Francisco; Harry K. Genant, MD: Professor of
Radiology, Medicine, and Orthopaedic Surgery, University of California, San Francisco.
Address reprint requests to Harry K. Genant. MD. Department of Radiology, University of California, San Francisco, CA
94143.
Submitted for publication November 8. 1982; accepted in
revised form May 23, 1983.
Arthritis and Rheumatism, Vol. 26, No. 11 (November 1983)
course, has been reported in Canada, France, Holland, and Sweden. A more disabling variety has been
noted in families from Czechoslovakia and Chile. The
third, reported in families from Spain, resembles spontaneous chondrocalcinosis in that the onset is later in
life and joint involvement is oligarticular.
The disease is caused by deposition of calcium
pyrophosphate dihydrate (CPPD) crystals in the hyaline and fibrocartilage of the skeletal system; however,
the mechanism for this is unknown. CPPD deposition
is associated with many diseases including hyperparathyroidism, hemochromatosis, hypomagnesemia, hypophosphatasia, Wilson’s disease, ochronosis, gout,
renal failure, and aging, but these associations give no
clear reason for the crystal deposition observed.
Moreover, the families with hereditary chondrocalcinosis show no signs of these diseases. Clues to the
etiology of hereditary CPPD depositions are found in
the decreased chondroitin-4-sulfate (8) and abnormal
pyrophosphate metabolism (9) observed in two of
these families.
We report another family with hereditary chondrocalcinosis. This family is afflicted with CPPD deposition disease similar to that found in the Canadian,
Swedish, Dutch, and French families. A cartilage
biopsy specimen obtained from 1 patient is unique in
that it shows loss of proteoglycans locally around the
chondrocytes, which may play a role in CPPD deposition.
PATIENTS AND METHODS
The family studied resides in the San Francisco Bay
Area and derives its heritage largely from Mexican-Indian
with some Chinese and Philippine ancestors. With the assistance of a family member, the family history was traced back
six generations to a Spanish man brought to Mexico at age 9.
RICHARDSON ET AL
1388
KEY
MALE
FEMALE
MALE, LESS THAN 21
FEMALE, LESS THAN 21
0
CHONDROCALCINOSIS
0 @ NKjATlVE HISTORY AND X-RAYS
0
a
DEATH -f
@ POYTIVE
HISTORY
0 NEGATIVE HISTORY
0 U N K N O W (Empty Center)
/
POSITIVEHISTORYB U T NEGATIVEX-RAYS0
BIOPSY TAKEN
Figure 1. Pedigree of a family featuring arthritis and chondrocalcinosis. Solid figures represent family members with chondrocalcinosis
demonstrated radiographically and clinically.
who married a Mexican Indian. One son from this union also
married a Mexican Indian and is the earliest generation
shown in the family pedigree. There are no Chilean ancestors and no further Spanish heritage. Sixty-four members
have been identified, with information available on 62. These
persons are distributed over 5 generations and include 49
adults and 15 children; there are 22 adult women and 27 adult
men. The age range of those living is 10-83 years.
History was obtained for 62 family members by
telephone interviews, and 23 of these responded to mailed
questionnaires. Outside medical records were available on 7
of those responding to the questionnaire. Nineteen of those
responding volunteered for further study; these included 11
adults and 8 children. Laboratory data were obtained from
13 of the volunteers with additional data available on 2
others from their records. Radiographs were obtained on 20
family members.
A routine medical history was taken and physical
examination performed on all members volunteering for
study. Careful attention was paid to symptoms of arthritis,
age at onset, joints involved, frequency of attacks, triggers
of attacks, characteristics of exacerbations, diet, medication, and associated illnesses. Radiographs of knees, pelvis,
shoulders, and wrists were taken of all adult volunteers. All
symptomatic joints were radiographed, and complete joint
surveys were obtained on 3 affected adults.
From 13 members, the following laboratory data
were obtained: calcium, phosphorus, glucose, blood urea
nitrogen, cholesterol, uric acid, protein, albumin, bilirubin,
alkaline phosphatase, lactic dehydrogenase, serum glutamic
oxaloacetic transaminase, creatinine, and sedimentation
rate. Serum magnesium levels were obtained on 9, and
parathyroid hormone levels on 7, using a radioimmunoassay
for the carbon terminal (10). Tissue typing for HLA antigens
A and B was performed on 9, and antinuclear antibody,
rheumatoid factor, serum protein electrophoresis, VDRL.
ceruloplasmin, iron and iron-binding capacity, and urinary
homogentisic acid were assayed on 4 volunteers.
A synovial and cartilage biopsy was obtained via
arthroscopy on 1 patient. The cartilage was formalin-fixed,
decalcified, and paraffin-embedded. Sections of this cartilage were stained with hematoxylin and eosin, alcian blue
(0.4M MgCl?. pH 1 . 3 , Safranin 0-fast green-iron hematoxylin (Lillie, 1965), and 0.04% toluidine blue, pH 1.0 (11).
Controls of the same stains included cartilage sections from
Table 1. Clinical features of 1 1 adults with f a rdial chondrocalcinosis
Patient
Sex
Age at
onset
Age at
study
Clinical
pattern*
MC I
M
29
54
A
MC I1
ET
M
F
16
32
35
53
A
C
ss
F
24
32
C
DT
EB
RB
JB
AS
M
28
35
19
21
20
29
D
M
M
M
M
51
29
30
A
A
A
46
C
M
F
41
47
41
76
A
FS
1s
C
Physical examinationt
Crepitus in knees, shoulders. and
elbows
Crepitus in knees
1ROM neck, shoulder, tender
MCP
Crepitus in knee. pain and crepitus
on neck flexion and rotation
Normal
Not done
Crepitus in knees
Not done
Crepitus in knees. J. ROM shoulders
Crepitus in knees
Not done
* A = pseudogout; C = pseudogout plus pseudo-osteoarthritis; D = pseudo-osteoarthritis.
t 1 ROM = limited range of motion; MCP = metacarpophalangeal joint.
HEREDITARY CHONDROCALCINOSIS
1389
Figure 2. Anteroposterior radiograph of the right hip demonstrating curvilinear hyaline cartilage calcification following the contour of
the femoral head and linear calcification of the fibrocartilage of the symphysis pubis (patient MC 11).
a normal femoral head, normal tibia1 plateau, and degenerative osteoarthritis from a proximal tibia.
RESULTS
The typical presentation of arthropathy in those
volunteering for the study was an acute inflammatory
arthritis triggered by trauma, exercise, or changes in
the weather. Attacks were self-limited and tended to
progress with time to a chronic arthropathy resembling
degenerative joint disease. Evidence for similar attacks was sought from the rest of the family by
telephone interviews, questionnaires, and personal
interviews. Of the 45 adults (ages 21-76) on whom
information was available, 22 (49%, 10 women and 12
men) had joint symptoms similar to those described
above, while 23 (51%) had negative histories. No
information was available on 4 adults. While the basis
for the data is entirely historical, it suggests that
approximately one-half of the adults in the family are
affected by an arthropathy, with no preference as to
sex.
The pedigree of the family is shown in Figure 1.
The features worthy of note in this diagram are: 1) no
consanguinity was detected, 2) male-to-male transmission was identified in two branches of the family, 3)
chondrocalcinosis is present in three consecutive generations, 4) in the third generation 4 of 5 descendants
(3 men and 1 woman) from an affected individual have
symptomatic chondrocalcinosis, and in those families
in which the third generation has reached adulthood, 2
of 3 and 2 of 5, respectively, had arthritis and chondrocalcinosis. The facts that both men and women are
affected, male-to-male inheritance can be demonstrated, no generations are skipped, and roughly one-half
of each generation is affected support the hypothesis
that the mode of inheritance is autosomal dominant
with a high degree of penetrance. It is also of interest
that 1 adult and 3 adolescents had clinical histories and
examination results consistent with familial arthropathy, but had no radiographic evidence of disease.
Of those 20 on whom radiographs and clinical
information were available, 11 had radiographic evidence of chondrocalcinosis. The clinical data on these
patients are shown in Table 1. This group consists of 8
1390
Figure 3. Anteroposterior radiograph of a left shoulder demonstrating typical curvilinear hyaline cartilage calcification at the glenohumeral joint (patient FS).
men and 3 women with an age range of 29-76 years.
The mean age of onset of symptoms is 28 years, with a
range of 16-47. Six of these family members described
attacks of acute inflammatory arthritis consistent with
the “pseudogout” presentation described by McCarty
(12). Four patients described acute inflammatory episodes superimposed on a chronic nondeforming arthropathy resembling degenerative arthritis, and 1
patient complained of chronic joint pain without an
inflammatory component.
Seven stated that exercise triggered attacks,
while 5 stated that trauma similarly initiated acute
inflammatory episodes. Three noted that changes in
weather precipitated attacks. Interestingly, 1 patient,
who also was hyperuricemic, stated that alcohol could
precipitate attacks, suggesting the possibility of concomitant gout. Since no joint fluid had been obtained
from this individual, a positive identification of the
crystals responsible for his arthritis was not possible.
No other dietary or drug factors were related to
symptoms.
Review of medical records obtained from the
private physicians of the patients, as well as histories
and physical examinations, failed to reveal any consistent underlying illnesses common to those affected.
Disorders found in the family, but restricted to single
individuals, included benign monoclonal gammopathy,
epilepsy, hypertension, gastric polyps, hyperuricemia,
RICHARDSON ET AL
gynecomastia of uncertain etiology, and tuberculosis
treated 12 years before this study.
Physical examinations performed on 8 involved
patients revealed no evidence of synovitis, joint effusion, or inflammation. Knee crepitation was found in 7,
and mild limitation of movement was noted in the
shoulders of 2 patients and in the neck of 1. Metacarpophalangeal tenderness was noted in 1 and pain on
rotation and flexion of the neck in another. Apart from
these findings, there was no evidence for hypertension, hyper- or hypothyroidism, ochronosis, tophi,
liver disease, or Kaiser-Fleischer rings.
The disease produced little to no disability; 1
patient (FS) reported only two attacks, another experienced only mild arthralgias of the knees and elbows,
and MC I1 occasionally missed work during flares.
None of the family is severely disabled. The majority
claim some relief of their symptoms with indomethacin, and colchicine has proved effective when taken
prophylactically.
Family members show radiographic evidence of
Figure 4. Less commonly found than the curvilinear hyaline cartilage calcification in Figure 3 is acromioclavicular calcification:
glenohumeral articular cartilage is also seen (patient ET).
HEREDITARY CHONDROCALCINOSIS
Figure 5. Lateral cervical spine radiograph reveals the intervertebra1 disc calcification generally seen only in those patients with
extensive involvement (patient MC I).
1391
fibrocartilage and hyaline cartilage calcification typical
of CPPD deposition (Figures 2-5). The prevalence of
chondrocalcinosis at the knee (Table 2), the wrist
(Table 2), and the shoulder (Figure 3) seen in this
family is similar to that described in other affected
families as well as in the sporadic cases of CPPD.
However, this family demonstrates a more widespread
pattern (Table 2) than the sporadic age-related form,
with acromioclavicular (Figure 4), cervical (Figure 5 )
and lumbar disc, and ankle involvement.
Several members of the family had no radiographic evidence of chondrocalcinosis but complained
of arthralgia similar to those with positive findings.
This subset includes 1 adult, age 27, and 4 teenagers.
Physical examination in 2 revealed abnormally fine
crepitus in 1 or more affected joints. Long-term followup will determine if the symptoms precede the radiographic findings.
Table 2 illustrates the relationship of joints with
radiographically detectable chondrocalcinosis to
symptomatic joints. Symptomatically, the knee was
affected most frequently, followed in decreasing frequency by the shoulders, elbows, wrists and cervical
spine, hands, ankles and lumbar spine, feet, and hips.
The knees were invariably symptomatic when involved with chondrocalcinosis, but only 1 of 5 hips
which demonstrated calcium deposition was symptomatic. Overall, of 35 joints with evidence of chondrocalcinosis, 9 (26%) were asymptomatic. There
were 6 joints which were symptomatic but had no
detectable calcification; 5 of these involved the spine
and 1 involved the shoulder.
Table 2. Comparison of clinical arthritis with radiographic chondrocalcinosis*
Patient
MC I
MC I1
ET
0
0
DT
EB
RB
JB
AS
FS
IS
0
0
0
+
.
0
0
ss
.
Total clinically
affected joints
*0
=
Cervical
spine
..+
Knee Wrist Hip
.
0
0
0
+
Lumbar
spine
Shoulder Elbow
+
0
0
0
-
-
-
+
-
+
0
0
0
0
0
0
6
4
8
0
-
+
0
0
10
6
1
symptomatic joint. no x-rays available; 0
=
Ankle
0
0
0
Foot
Hand
0
0
0
0
0
0
0
0
0
+
.
O
0
7
0
0
0
4
2
5
chondrocalcinosis in symptomatic joint;
+ = positive x-rays, but no symptoms; - = negative x-rays, but positive history.
1392
RICHARDSON ET AL
Figure 6 . Patient MC 11: Synovial biopsy specimen examined microscopically with compensated polarized light
demonstrating rhomboidal, weakly positively birefringent crystals typical of calcium pyrophosphate dihydrate. Note
crystals present in synovial membrane seen as white structures (arrowhead) on hematoxylin and eosin stain (original
magnification x 250).
Diseases known to be associated with CPPD
deposition were screened by a series of laboratory
tests. Specifically, hyperparathyroidism was evaluated with serum calcium, PO4, and parathyroid hormone
levels. Hemochromatosis was screened for with serum
iron and total iron-binding capacity, hypophosphatasia
with serum alkaline phosphatase, hypomagnesemia
with serum magnesium, gout with serum urate, ochronosis with urinary homogentisic acid, Wilson’s and
other inflammatory arthritides with antinuclear antibody, rheumatoid factor, erythrocyte sedimentation
rate (ESR), and serum protein electrophoresis. No
consistent abnormalities were found. One patient each
had the following abnormal test results: positive
VDRL, ESR 28, elevated serum glutamic oxaloacetic
transaminase.
Because of a reported association of familial
chondrocalcinosis with HLA antigens A2 and Bw35
(13), HLA typing was performed on 8 volunteers, 5
with and 3 without chondrocalcinosis. No strong HLA
associations were found, although the numbers are
small. Specifically, no Bw35 was identified, and of
those with A2, 3 had chondrocalcinosis and 2 did not.
Synovial and cartilage biopsy specimens were
obtained from I patient via arthroscopy. Figure 6
shows a portion of the synovial biopsy specimen
under compensated polarized light microscopy. The
crystal shows weakly positive birefringence and has
the characteristic rhomboidal shape of calcium pyrophosphate dihydrate. This, coupled with the characteristic radiographic findings, strongly suggests that
the arthropathy seen in this family is due to CPPD
deposition.
The patient’s cartilage biopsy specimen showed
defects in the articular cartilage as seen in CPPD.
These defects consisted of irregularly shaped spaces
within the cartilage in the middle zone (14) compatible
with spaces resulting from CPPD crystals that dissolved during decalcification (Figure 7). Alcian blue,
Safranin 0, and toluidine blue stains all demonstrated
1393
HEREDITARY CHONDROCALCINOSIS
Figure 7. Patient MC 11’s cartilage with numerous irregularly shaped spaces in the middle zone. These are compatible with
spaces resulting from CPPD crystals that have dissolved during decalcification procedures. Note the focal loss or absence
of staining adjacent to the defects (alcian blue, original magnification X 188).
A
B
Figure 8. A, Patient MC 11’s cartilage with “halo” surrounding chondrocytes (alcian blue. original magnification x 125). B, Same cartilage as in
A, but with Safranin 0 stain (original magnification x 235).
1394
RICHARDSON ET AL
loss or absence of matrix staining around chondrocytes in a “halo” pattern and decreased staining
within lacunae in the middle and calcification zones
(Figures 8A and B). In contrast, the normal controls
showed no loss of staining and actually showed increased staining around chondrocytes and within lacunae in most regions (Figure 9). Also, an increase in
diffuse staining of matrix in the deeper zones was seen
in the normal, but not in the patient’s, specimen. The
cartilage from the patient with degenerative osteoarthritis showed decreased staining of the matrix, but
this occurred in a mosaic pattern with no “halos”
around chondrocytes (Figure 10).
DISCUSSION
Figure 9. ~~~~~l cartilage; note absence of ‘‘halo” around chondrocytes (alcian blue, original magnification x 188).
The family described above demonstrates the
clinical, radiographic, and pathologic findings of a
hereditary form of chondrocalcinosis. Clinical evaluation indicates that the arthropathy is inherited in an
aUtOSOmal dominant fashion and iS characterized by
onset in the second to fifth decades of either episodes
Figure 10. Degenerative joint disease with mosaic pattern. Note absence of distinct “halos” (alcian blue, original
magnification x 75).
HEREDITARY CHONDROCALCINOSIS
of acute inflammatory arthritis or a clinical picture
resembling degenerative joint disease. Family members have radiographic evidence of widespread chondrocalcinosis, more extensive than that seen in the
sporadic age-related form (15), and involving most of
the hyaline and fibrocartilage of the skeletal system.
Interestingly, not all the affected cartilage is
symptomatic. Cartilage was calcified in 5 of 5 hips
examined, but only 1 patient complained of hip pain. It
is possible that other asymptomatic joints, if examined, would also show signs of chondrocalcinosis. The
question of why certain affected joints manifest signs
of arthritis while others do not remains unanswered.
The cause of the arthritis in the affected family
members is CPPD deposition. This is supported by the
radiographic findings of linear calcification characteristic of CPPD deposition in all affected family members and by the demonstration of rhomboidal, weakly
positively birefringent crystals in 1 patient.
A family reported from Czechoslovakia demonstrated an HLA disease linkage to A2 and Bw35. We,
as well as others (1,6), failed to confirm such a linkage.
A unique finding in this report is the cartilage
morphology. Staining with alcian blue in the acidic pH
range, as well as Safranin 0, correlates with the
presence of intact proteoglycan structure ( I 1,16). Intact proteoglycan protects cartilage from calcification
with hydroxyapatite (17,18) and theoretically may
prevent CPPD deposition as well (19). Disorders in
which this structure is interrupted correlate with loss
of staining as well as loss of protection from crystal
formation (1 1,17,18).This specimen demonstrated loss
of the proteoglycans in “halos” around the chondrocytes, with intact staining between the chondrocytes.
This pattern suggests that the proteoglycan has been
successfully synthesized, but for unknown reasons has
been lost and not replaced around the chondrocytes.
Such changes were not seen in normal or degenerative
specimens. Indeed, the first change seen in degenerative joint disease is usually an increase in glycosaminoglycan synthesis, followed by a diminished net synthesis as the chondrocytes fail (20). This pattern
typically results in an early increase in stains for the
proteoglycan around the chondrocytes, followed by
generalized loss throughout the affected areas of cartilage (1 1,20).
The observed pattern of proteoglycan loss in
the perichondrocyte areas is striking. The family reported by Reginato et al (14) demonstrated focal areas
of decreased staining, but no relation to chondrocytes
was noted. The study reported by Bjelle (21) specifi-
1395
cally noted a rim of normally stained cartilage around
the chondrocytes, with areas of decreased staining
between the chondrocytes.
It is tempting to speculate that the areas of
hypopigmentation observed around the chondrocytes
represent degradation of proteoglycans. This would
explain the normal staining in the matrix between the
lacunae. Loss of proteoglycan would then lead to
CPPD crystal deposition by loss of the calcium chelation and protection from crystal formation normally
provided by the chondroitin sulfate present in intact
cartilage. Further characterization will be facilitated
by obtaining more tissue for biochemical studies.
REFERENCES
1 . Gaudreau A, Camerlain M, Piborot ML, Beauregard G,
Lebiun A, Petitclerc C: Familial articular chondrocalcinosis in Quebec. Arthritis Rheum 24:611-615, 1981
2. Zitnan D, Sitaj S: Chondrocalcinosis articularis. Ann
Rheum Dis 22:142-168, 1963
3. Van de Korst JK, Geerards J, Driessens FCM: A
hereditary type of idiopathic articular chondrocalcinosis. Am J Med 56:307-314, 1974
4. Rodriguez-Valverde V, Tintare T, Zaniga M, Pena J,
Gonzales A: Familial chondrocalcinosis: prevalence in
northern Spain and clinical features in five pedigrees.
Arthritis Rheum 23:471-478, 1980
5. Reginato AM, Valenzuela FR, Martinez VC, Passano G,
Daza SK: Polyarticular and familial chondrocalcinosis.
Arthritis Rheum 13: 197-21 1 , 1970
6. Gaucher A, Faure G, Netter P, Pourel J, Raffoux C,
Streiff F, Tongio MM, Mayer S: Hereditary diffuse
articular chondrocalcinosis. Scand J Rheumatol 6:216221, 1977
7. Bjelle A, Edvinsson U, Hagstam A: Pyrophosphate
arthropathy in two Swedish families. Arthritis Rheum
25:66-73, 1982
8. Bjelle AO: The glycosaminoglycans of articular cartilage
in calcium pyrophosphate dihydrate crystal deposition
disease. Calcif Tissue Res 12:37-46, 1973
9. Lust G, Faure G, Netter P, Gaucher A, Seegmiller JE:
Evidence of a generalized metabolic defect in patients
with hereditary chondrocalcinosis. Arthritis Rheum
24:1517-1521, 1981
10. Arnaud CD, Tsao HS, Littledike T: Radioimmunoassay
of human parathyroid hormone in serum. J Clin Invest
50121-34, 1971
1 1 . Christenssen SB, Reimann I: Differential staining of
glycosaminoglycans in the matrix of osteoarthritis cartilage. Acta Pathol Microbiol Scand (Sect A) 88:61-68,
1980
12. McCarty DJ: Calcium pyrophosphate dihydrate crystal
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deposition disease (pseudogout syndrome)--clinical aspects. Clin Rheum Dis 3:61-89, 1977
Nyulassy S, Stefanovic J, Sitaj S, Zitnan D: HL-A
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Reginato AJ,Schumacher HR, Martinez VA: The articular cartilage in familial chondrocalcinosis. Arthritis
Rheum 17:977-992, 1974
Resnick D, Niwayama G , Goergen TG, Utsinger RD,
Shapiro RF, Hagelwood DH, Wiesner KB: Clinical,
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RICHARDSON ET AL
17. DiSalvo J, Schubert M: Specific interaction of some
cartilage protein polysaccharides with freshly precipitating calcium phosphate. J Biol Chem 242:705-710, 1967
18. Howell DS, Pita JC, Marquez JF, Gatter RH: Demonstration of macromolecular inhibitor of calcification and
nucleation factor in fluid from calcifying sites in cartilage. J Clin Invest 48:630, 1969
19. Rynes RZ: Calcium pyrophosphate dihydrate crystal
deposition. J Rheumatol 75-7, 1980
20. Thompson RC, Oegema TR: Metabolic activity of articular cartilage in osteoarthritis. J Bone Joint Surg
6 1 A:407-4 16, 1979
21. Bjelle AO: Morphological study of articular cartilage in
pyrophosphate arthropathy. Ann Rheum Dis 3 1:449450, 1972
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