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MRI Web Clinic - June 2024

Calcium Pyrophosphate Dihydrate (CPPD) Crystal Deposition Disease

Ramon P. Saucedo, M.D., Brady Huang, M.D., Karen Y. Cheng, M.D., Donald Resnick, M.D.

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Clinical History: 

An active, previously healthy, 65-year-old man presents with a 3-week history of atraumatic left knee pain. A frontal radiograph (1a), proton density fat-suppressed sagittal MR image (1b), proton density fat-suppressed axial MR image (1c), and selected arthroscopic images (1d and 1e) are provided. What are the findings? What is the diagnosis?


The knee radiograph demonstrates medial and lateral femorotibial compartment chondrocalcinosis, (2a, red arrows), and mild medial femorotibial compartment joint space narrowing. Proton density fat-suppressed sagittal (2b) and proton density fat-suppressed axial MR images (2c) demonstrate high grade trochlear cartilage loss with accompanying subchondral marrow edema and cystic change (red arrows). Selected arthroscopic images demonstrate mineralization of the medial (2d) and lateral (2e) menisci (red arrows). Synovial biopsy at the time of arthroscopy showed crystal deposits consistent with calcium pyrophosphate dihydrate crystal deposition disease.


Calcium pyrophosphate dihydrate crystal deposition disease.



Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is one of the most common articular disorders, particularly in the elderly population. The most recognized imaging feature of this disorder is cartilage calcification, termed chondrocalcinosis. Chondrocalcinosis alone, however, is not the only significant imaging feature of this disease. Additional characteristic imaging findings include other intraarticular and periarticular calcifications and structural joint damage, the latter termed pyrophosphate arthropathy. In fact, the pattern and distribution of pyrophosphate arthropathy are distinctive and can often be differentiated from the features of osteoarthrosis to allow an accurate diagnosis of CPPD crystal deposition disease even in the absence of chondrocalcinosis.1

Seminal work by McCarty and others in 1961 and 1962 discovered non-urate crystals in the joint fluid of patients experiencing gout-like attacks of arthritis, crystals that were subsequently identified as CPPD crystals by their x-ray diffraction powder pattern.2,3

Analysis of clinical and radiographic findings demonstrated that this same disease process had been described previously as chondrocalcinosis polyarticularis. Therefore, it became clear that patients with a distinctive gout-like pattern of arthritis (i.e., pseudogout syndrome) had crystal accumulation within joints (CPPD crystal deposition) that could cause cartilage calcification (chondrocalcinosis).



Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease: General term for a disorder characterized by the presence of CPPD crystals in and around joints.

Pseudogout: Term applied to one of the clinical patterns that may be associated with crystal deposition—intermittent acute attacks of arthritis that simulate those of gout.

Chondrocalcinosis: Term reserved for pathologically or radiographically evident cartilage calcification.

Articular and periarticular calcification: Term used for pathologically or radiographically evident calcification in and around joints.

Tophaceous pseudogout: Term used for soft tissue mass-like deposits of CPPD crystals.

Pyrophosphate arthropathy: Term used to describe a peculiar and specific pattern of structural joint damage occurring in CPPD crystal deposition disease, with some features that overlap with those of degenerative joint disease.


Clinical Patterns

CPPD crystal deposition disease affects both men and women and is generally observed in middle-aged and elderly patients.4 A pattern of disease simulating gout and therefore designated pseudogout occurs in about 10 to 25% of symptomatic patients with CPPD crystal deposition disease.5 This pattern is characterized by acute or subacute self-limited attacks of arthritis and may be precipitated by trauma, surgery, medical illness, or intraarticular injection.6 A second clinical pattern characterized by almost continuous attacks of arthritis simulating rheumatoid arthritis (i.e., pseudorheumatoid arthritis) is seen in about 5% of symptomatic patients.7,8 In 50-60% of symptomatic patients, chronic articular disease with or without acute exacerbations simulates osteoarthrosis (i.e. pseudo-osteoarthrosis).8 Additional less frequent patterns can mimic neuropathic osteoarthropathy1 and spondyloarthropathy.9 It should be emphasized, however, that most persons with CPPD crystal deposition disease are asymptomatic, with the deposits likely occurring as a consequence of aging and detected as an incidental and unexpected finding on imaging studies done for unrelated reasons.4

Familial forms of CPPD crystal deposition disease also exist. The two main forms of familial CPPD crystal deposition disease correspond to mutations at a locus on chromosome 8q (CCAL1) and mutations at a locus on chromosome 5p (CCAL2).10,11 These mutations are inherited in an autosomal dominant fashion, with a high degree of penetrance.10 Mutations in the ankylosis human analog (ANKH) gene on chromosome 5p are implicated in the CCAL2 subtype of familial CPPD crystal deposition disease, whereby ANKH protein activity is enhanced, elevating extracellular pyrophosphate levels and promoting the formation of CPPD crystals.10 Mutations in osteoprotegerin (OPG) have recently been implicated in the CCAL1 subtype of familial CPPD crystal deposition disease.12 Interestingly, this subtype of familial CPPD crystal deposition disease does not result in alterations in the ANKH signaling pathway, suggesting that CPPD crystal deposition can occur via multiple molecular pathways that may or may not intersect.11,12 The mechanism in which OPG mutations lead to CPPD crystal deposition is less understood, with a possible role for altered osteoclastogenesis in subchondral bone as a major contributor for degenerative joint disease.12 CCAL1 subtype familial CPPD crystal deposition disease generally presents with the onset of chondrocalcinosis well before the development of significant structural joint disease, whereas CCAL2 subtype cases demonstrate a simultaneous onset of generalized degenerative disease and chondrocalcinosis.12


Associated Diseases

A bevy of medical conditions have been reported in varying degrees of association with CPPD crystal deposition disease, with the strongest evidence related to its association with hyperparathyroidism, hemochromatosis, hypophosphatasia, and hypomagnesemia (including Bartter and Gitelman syndromes).

Classic musculoskeletal manifestations of hyperparathyroidism are well-known, including osteitis fibrosa cystica, salt-and-pepper degranulation of the calvarium, distal tapering of the clavicles, subperiosteal resorption, and brown tumors.13 With regard to hyperparathyroidism, it has been postulated that the proteoglycans that inhibit CPPD crystallization might be overwhelmed by systemic hypercalcemia and that altered cartilage metabolism in these patients promotes abnormally high enzymatic activity whereby calcium and pyrophosphate-containing material accumulate in the joints.13 A pseudogout attack after parathyroid surgery may be triggered by an abrupt decrease in serum calcium concentration in synovial fluid, making CPPD crystals more soluble so that they are shed into the synovial space.14,15

Hemochromatosis, a relatively common genetic disorder of iron metabolism with variable penetrance, has a long established association with CPPD crystal deposition disease,16 with 20-30% of patients with hereditary hemochromatosis shown to have CPPD crystal deposition disease.17 End-organ damage is secondary to increased intestinal absorption of iron and decreased hepcidin levels resulting in iron deposition in tissues throughout the body.16 With regard to the association of hemochromatosis with CPPD crystal deposition disease, both disease processes may share alterations in signaling pathways implicated in bone metabolism (e.g., alterations in osteoblast and osteoclast activity), suggesting some mechanistic overlap.18,19

Hypophosphatasia is a rare heterogeneous inborn error of bone metabolism caused by mutations in the ALPL gene encoding the tissue-nonspecific alkaline phosphatase isoenzyme (TNAP).20 Inorganic phosphate (PPi) is one of the physiologic substrates of TNAP, which accumulates in the setting of TNAP deficiency.21 Excess PPi supports the deposition of pyrophosphate and calcium in a crystallized form as CPPD crystals.20 CPPD crystal deposition is highly associated with hypophosphatasia, with one case series demonstrating an association of 71%.22

Bartter and Gitelman syndromes are two distinct hereditary disorders resulting in defects in renal tubular concentration of sodium, potassium, and chloride23 with resultant hypokalemia and metabolic alkalosis.24 These two disorders are also associated with CPPD crystal deposition disease. Hypomagnesemia is a hallmark of Gitelman syndrome and variably associated with subtypes of Bartter syndrome.23,25 Magnesium is a cofactor of various pyrophosphatases, including alkaline phosphatase.26 Decreased alkaline phosphatase activity due to hypomagnesemia could theoretically result in high extracellular levels of inorganic phosphate (PPi), predisposing to CPPD crystal deposition.26 It is thought that the classic association between Bartter syndrome and CPPD crystal deposition may have significant overlap with features of Gitelman syndrome, as no cases of Bartter syndrome without hypomagnesemia have been associated with CPPD crystal deposition disease.24


Imaging-Pathologic Correlation


Chondrocalcinosis is the hallmark feature of CPPD crystal deposition disease, whereby these crystals are deposited in hyaline cartilage or fibrocartilage, or both. Chondrocalcinosis is manifest by radiodense regions in the cartilage that are visible with conventional radiography and CT, and by foci of low signal intensity on MR images. Chondrocalcinosis involving fibrocartilage is most commonly seen in the menisci of the knee, symphysis pubis, triangular fibrocartilage of the wrist (Figures 3 and 4), annulus fibrosus of the intervertebral disc, acetabular labrum, and glenoid labrum. Hyaline cartilage calcification is most frequently seen in the knee, elbow, wrist, hip, and glenohumeral joints.1,27 Fibrocartilaginous calcifications appear as thick, shaggy, irregular radiodense areas, particularly within the central aspect of the joint. Hyaline cartilaginous deposits may be thin, linear, curvilinear, or punctate and are separate from and parallel to the subchondral bone plate.27

Click on the image thumbnail to access the full image and see image-specific details.

Figure 4. Cadaveric axial section through the wrist demonstrates CPPD crystal deposition at the hamate attachment of the transverse carpal ligament (red arrow).


Synovial/Capsular Calcification:

Calcification within the synovial membrane is a common feature of CPPD crystal deposition disease. Synovial deposits are most frequent in the wrist, particularly about the radiocarpal and distal radioulnar joints, knee, and metacarpophalangeal and metatarsophalangeal joints.1 Such deposits may mimic idiopathic synovial chondromatosis.1 CPPD crystal deposition within the joint capsule is most commonly observed in the elbow and metatarsophalangeal joints but is also observed in the metacarpophalangeal and glenohumeral joints.28

Tendon/Bursal/Ligament Calcification:

Calcification is most often observed in the Achilles, triceps, quadriceps, gastrocnemius, and supraspinatus tendons, as well as in the subacromial-subdeltoid bursa.28 These calcifications are typically more linear and elongated than those seen in calcium hydroxyapatite crystal deposition disease (Figure 5).

Soft Tissue Calcification (Tophaceous Pseudogout):

Tophaceous pseudogout is a term reserved for tumor-like or mass-like deposition of CPPD crystals within the soft tissues, sometimes distant from articular and periarticular structures.29 Imaging characteristics are nonspecific, with the differential diagnosis including such entities as tophaceous gout, idiopathic or secondary tumoral calcinosis, and benign or malignant neoplasms.29,30

Patients with tophaceous pseudogout may not show other stigmata of CPPD crystal deposition disease (e.g., chondrocalcinosis or pyrophosphate arthropathy). Soft tissue sampling yielding weakly positive birefringent crystals with polarized microscopy is pathognomonic for tophaceous pseudogout, as malignant or nonmalignant cartilaginous neoplasms are not associated with this phenomenon.29,30

The temporomandibular joint is the most common site of tophaceous pseudogout, followed by the hand, foot, wrist (Figure 6), cervical spine, and hip.29 Lower extremity involvement can be seen about the ankle30 and knee (Figure 7) as well.

Structural Joint Damage (Pyrophosphate Arthropathy):

The structural joint changes associated with CPPD crystal deposition disease are both common and characteristic and may appear without adjacent or distant articular calcification. Pyrophosphate arthropathy is most frequent in the knee, wrist, and metacarpophalangeal joints.28 Distribution is usually bilateral, although symmetric changes may not be present. Pyrophosphate arthropathy is similar to osteoarthrosis with regard to joint space narrowing and subchondral bone sclerosis and cyst formation; however, it differs in five respects:

  1. Unusual articular distribution: Although pyrophosphate arthropathy is seen in weight-bearing joints, such as the knee and hip, it is also apparent in sites that are less commonly involved in degenerative joint disease, such as the wrist, elbow, and glenohumeral joint.28
  2. Unusual intraarticular distribution: The distribution of pyrophosphate arthropathy in certain joints is characteristic.1,28 Isolated or significant involvement of the radiocarpal, triscaphe, patellofemoral, and talocalcaneonavicular joints may signify CPPD crystal deposition disease.
  3. Prominent subchondral cyst formation: In contradistinction to subchondral cystic change encountered with osteoarthrosis, the cysts associated with pyrophosphate arthropathy are numerous and may reach considerable size.28
  4. Destructive bone changes that are severe and progressive: Pyrophosphate arthropathy may be associated with extensive and rapid subchondral bone collapse and fragmentation, with the appearance of single or multiple intraarticular bodies simulating neuropathic osteoarthropathy.1,28
  5. Variable osteophyte formation: Large, irregular bony excrescences have been noted in some patients with pyrophosphate arthropathy, whereas joint space narrowing and bone sclerosis and fragmentation have been unaccompanied by osteophyte formation in others.28


Specific Sites of Involvement


Calcification in the wrist is observed most commonly in the triangular fibrocartilage;31,32 hyaline cartilage of the radiocarpal, midcarpal, and common carpometacarpal joints; synovium; and ligamentous structures, particularly the scapholunate and lunotriquetral interosseous ligamentous complexes.31,32 Carpal malalignment with scapholunate diastasis can occur, with disruption of the intervening interosseous ligament, as well as other intrinsic and extrinsic ligaments of the wrist31 (Figure 8).

The wrist arthropathy of CPPD crystal deposition disease demonstrates a predilection for the radiocarpal compartment.1,28 Joint space narrowing, subchondral bone sclerosis, and subchondral cystic change are observed, especially in the radioscaphoid portion of the joint with enlargement and deepening of the scaphoid fossa in the distal articular surface of the radius. Progressive changes include widening of the scapholunate interosseous space, narrowing of the lunate-capitate space, and abnormal tilting of the lunate, findings simulating those that occur in cases of post-traumatic scapholunate advanced collapse (SLAC)27 (Figure 9). These changes are in contradistinction to osteoarthrosis, in which degenerative changes are more typically seen in a first ray distribution.


The metacarpophalangeal joints are frequently affected in CPPD crystal deposition disease, most commonly the second and third metacarpophalangeal joints,28,31 often in a bilateral distribution.  Radiographic abnormalities in this location include cartilaginous, capsular, and synovial calcifications, as well as pyrophosphate arthropathy (Figure 10). This is in contradistinction to osteoarthrosis, in which degenerative changes predominate in the interphalangeal joints. Absence of bone erosions differentiates CPPD crystal deposition disease from rheumatoid arthritis. Hemochromatosis can demonstrate similar findings in the second and third metacarpophalangeal joints; however, involvement of the first, fourth and fifth metacarpophalangeal joints and hook-like osteophytes on the radial aspect of the metacarpal heads are more common in hemochromatosis33(Figure 11).


The knee is the most commonly affected joint in CPPD crystal deposition disease.28 Chondrocalcinosis and synovial calcification may be seen alongside tendinous and ligamentous deposits in the quadriceps, gastrocnemius, and cruciate and collateral ligaments34(Figure 12). Chondrocalcinosis of the menisci and hyaline cartilage with gastrocnemius tendinous calcification is a characteristic appearance1,35(Figure 13).

Pyrophosphate arthropathy predominates in the medial femorotibial compartment, with the patellofemoral compartment being the second most commonly involved compartment.36 Isolated or severe patellofemoral or lateral femorotibial compartment alterations, especially in men, are characteristic of CPPD crystal deposition disease28 (Figures 14 and 15).


Fibrocartilaginous calcification of the acetabular labrum and hyaline cartilage calcification can be observed in CPPD crystal deposition disease28 (Figure 16). Joint space narrowing may be confined to the superolateral aspect of the articulation or be seen throughout the entire joint, simulating osteoarthrosis and rheumatoid arthritis, respectively. Prominent subchondral cyst formation may be present. Rapid and extensive destruction of the femoral head and acetabulum may occur as well, simulating neuropathic osteoarthropathy (Figure 17).1


CPPD crystal deposition disease is accompanied by intervertebral disc calcification, with deposits initially appearing peripherally in the outer fibers of the annulus fibrosus.28 Deposits can be seen in other spinal tissues, including the ligamentum flavum, posterior longitudinal ligament, interspinous and supraspinous ligaments, and interspinous bursae.37,38

Intervertebral disc space narrowing is a common finding in CPPD crystal deposition disease, which may be widespread and associated with pronounced vertebral body sclerosis.37 Destructive changes in adjacent vertebral bodies may be present as well, simulating infection or neuropathic osteoarthropathy.37

At the atlantoaxial joint, CPPD crystal deposition is most typically seen in the posterior median atlantoaxial joint, causing inflammation about the odontoid process (so-called crowned dens syndrome)37,38,39 (Figure 18). The resulting mass may compress the spinal cord and predispose to dens fractures and atlantoaxial subluxation39 (Figure 19).

Other sites:

The foot and ankle are less frequent sites of CPPD crystal deposition disease. As with the aforementioned sites of involvement, chondrocalcinosis can be observed without (Figure 20) or with (Figure 21) changes related to pyrophosphate arthropathy. Case reports in the literature have demonstrated pseudoneuropathic pseudogout in the midfoot40 and tophaceous pseudogout in the hindfoot.30

As noted previously, the temporomandibular joint is the most common site of tophaceous pseudogout.29,41 The sternoclavicular joint is an additional site of CPPD crystal deposition, with prevalence increasing with advancing age.42,43

Advanced Imaging Methods


With CT, many of the findings of CPPD crystal deposition disease that are seen on conventional radiographs, namely chondrocalcinosis, periarticular calcification, and soft tissue calcification, are visible with characteristic increased Hounsfield unit density. The advantages of CT versus conventional radiography are most apparent in the assessment of the spinal manifestations of this disease. Of note, dual energy CT has been shown to be less sensitive in the detection of CPPD crystals versus that of monosodium urate crystals44,45(Figure 22).

Click on the image thumbnail to access the full image and see image-specific details.

Figure 22. Monosodium urate crystal deposition (gout). Reconstructed dual energy 3D image of the knee demonstrates monosodium urate crystal deposition (green foci) at the lateral patellar facet, lateral femoral condyle, lateral tibial plateau, and fibular head (red arrows), the differentiation of which is made possible by the principle that material containing elements of higher atomic number (e.g., calcium) demonstrates higher attenuation at higher photon energies than material containing elements of lower atomic number (e.g., monosodium urate). (Case, courtesy of Diego Lessa, M.D.)


MR Imaging:

CPPD crystal deposition is less apparent with MR imaging when compared with conventional radiography or CT. Chondrocalcinosis may be manifest by areas of low signal within the articular cartilage, though MR imaging may severely underestimate the extent of such calcification when compared with radiographs.46 Additionally, certain sequence parameters may increase the signal intensity of fibrocartilaginous structures such as the knee menisci, worsening the sensitivity and specificity for MR detection of meniscal tears.47 More recent literature suggests a role for ultrashort time to echo (UTE) sequence imaging in the evaluation of CPPD crystal deposition in the knee.48

While MR imaging is not particularly sensitive or specific with regard to screening for CPPD crystal deposition, this modality’s excellent soft tissue contrast and display of intraarticular and periarticular structures provide a vital tool in the evaluation of pyrophosphate arthropathy and tophaceous pseudogout.


Diagnostic musculoskeletal ultrasound allows identification of CPPD crystal deposits in peripheral joints and within the soft tissues.49 Such deposits are characterized by either thin hyperechogenic foci paralleling the joint surface or focal nodular hyperechogenic foci on greyscale ultrasonography.49 Doppler ultrasonography allows identification of synovitis in affected joints (Figures 6 and 20). Reports indicate that ultrasonography has high specificity and sensitivity for detection of chondrocalcinosis (greater than 90 and 80 percent, respectively45,49); however, it must be noted that the success of this technique is highly operator dependent.


Differential Diagnosis

Abnormal Calcification:

Abnormal intraarticular and periarticular calcification is characteristic of basic calcium phosphate crystal deposition disease, also designated calcium hydroxyapatite crystal deposition disease. This condition may occur on an idiopathic basis, as an inherited disorder, or as a complication of a number of underlying disorders, especially collagen vascular diseases, renal osteodystrophy, hyperparathyroidism, and hypervitaminosis D.50 In contradistinction to CPPD crystal deposition, basic calcium phosphate deposits often begin as poorly defined cloudlike areas of calcification, eventually becoming more sharply delineated.50 The most common site of calcification in this disorder is within the tendons of the rotator cuff, often at or near the footprint of the involved tendon (Figures 23 and 24). Although calcification of the rotator cuff tendons can also be seen in cases of CPPD crystal deposition disease, this is an infrequent site of involvement and the resulting calcifications are linear or curvilinear in appearance, sometimes extending over a long segment of the tendon.

Gout, a frequently encountered crystalline arthropathy, does not typically demonstrate chondrocalcinosis, although there are reports of the association of gout with CPPD crystal deposition.51 Additionally, calcification of monosodium urate deposits has been noted, especially in patients with chronic renal disease.27 Uric acid crystals are well-displayed with dual-energy CT scanning.45 Erosions are characteristic of gout and are not typical in cases of CPPD crystal deposition disease.

Tophaceous pseudogout can sometimes provide a diagnostic dilemma, necessitating differentiation from chondroid or other mineralized neoplasms. Tissue sampling may be required (Figure 25).


Conditions That Mimic Pyrophosphate Arthropathy:

Pyrophosphate arthropathy closely resembles degenerative joint disease, although, as indicated previously, there are a few characteristics of pyrophosphate arthropathy that are relatively distinctive. These include the involvement of specific joints or regions of joints that are uncommonly involved in osteoarthrosis and some distinctive morphologic features that include extensive bone sclerosis, subchondral cysts that are often multiple and sometimes large, variable osteophyte formation, and, in some cases, rapid and progressive joint destruction (Figure 26). These findings, however, may simulate other disorders such as neuropathic osteoarthropathy, steroid-induced arthropathy, osteonecrosis, and infection.1,28




No disease-modifying therapies currently exist to reduce CPPD crystal deposits; treatment is aimed at controlling the inflammatory response and decreasing the frequency and severity of symptoms.52 Current treatment methods include non-steroidal anti-inflammatory drugs, colchicine, and intra-articular corticosteroid injections.

Refractory cases may be treated with immune modulators. Anakinra, an interleukin-1R antagonist, has a proven efficacy in autoimmune inflammatory conditions and has been shown to effectively treat refractory symptomatic CPPD crystal deposition disease.52 Tocilizumab, an interleukin-6 antagonist, demonstrates similar promise.52



CPPD crystal deposition disease is a well-known and common disease process with specific articular, periarticular, and soft tissue manifestations as detailed throughout this Web Clinic. Conventional radiography, CT, and ultrasonography can each be used to allow identification of regions of abnormal calcification and to display sites of pyrophosphate arthropathy. MR imaging is less helpful in the analysis of sites of abnormal calcification but can provide useful diagnostic information in cases of tophaceous pseudogout or spinal involvement. When interpreting MR imaging examinations, meticulous review of all the patient’s imaging studies, including x-ray based examinations, is essential to establish the correct diagnosis of CPPD crystal deposition disease. Although other processes can lead to calcific deposits simulating those of CPPD crystal deposition disease, knowledge of the typical sites of involvement and the distinctive morphologic features should allow accurate diagnosis of this very common crystal deposition disease in most cases.





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