Calcium Pyrophosphate Deposition (CPPD) Disease Workup

Updated: Apr 03, 2021
  • Author: Constantine K Saadeh, MD; Chief Editor: Herbert S Diamond, MD  more...
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Approach Considerations

Revised diagnostic criteria for calcium pyrophosphate deposition (CPPD) disease are from the Primer on Rheumatic Diseases (1997) and are used with permission from the Arthritis Foundation. The criteria are as follows [22] :

  • Criterion I - Demonstration of calcium pyrophosphate crystal deposition in tissue or synovial fluid by definitive means (eg, characteristic radiographs, diffraction analysis, or chemical analysis)

  • Criterion IIa - Identification of monoclinic or triclinic crystals showing no or weakly positive birefringence by compensated polarized light microscopy

  • Criterion IIb - Presence of typical radiographic calcifications

  • Criterion IIIa - Acute arthritis, especially of knees or other large joints

  • Criterion IIIb - Chronic arthritis, especially of knee, hip, wrist, carpus, elbow, shoulder, or metacarpophalangeal (MCP) joint, particularly if accompanied by acute exacerbation

In criterion IIIb, chronic arthritis shows the following features, which are helpful in differentiating it from osteoarthritis:

  • Uncommon sites - Wrist, MCP joint, elbow, shoulder

  • Radiographic appearance - Radiocarpal or patellofemoral joint-space narrowing, especially if isolated (eg, patella wrapped around the femur)

  • Subchondral cyst formation

  • Severity of degeneration - Progressive, with subchondral bony collapse and fragmentation with formation of intra-articular, radiodense bodies

  • Osteophyte formation - Variable and inconsistent

  • Tendon calcifications - Especially triceps, Achilles, obturators

Criteria-based categories include the following:

  • Definite disease - Criterion I or IIa plus IIb must be fulfilled
  • Probable disease - Criterion IIa or IIb must be fulfilled
  • Possible disease - Criterion IIIa or IIIb should alert the clinician to the possibility of underlying calcium pyrophosphate deposition


Arthrocentesis is the most important procedure to perform, especially in patients with acute pseudogout. The acquired fluid can be examined using compensated polarized microscopy, and fluid cultures can be performed.

Histologic Findings

Histologic changes associated with CPPD correspond to calcium deposits and to inflammation due to cartilage fragments. These changes are nonspecific, but calcium deposits inside the chondrocartilage are perhaps the most typical finding in patients with this condition. The pathognomonic finding with compensated polarized microscopy is the presence of weakly positively birefringent crystals, typically intracellular, that are usually rhomboid in shape.

Associated conditions

A number of conditions have been associated with CPPD. When CPPD is diagnosed, especially in a patient younger than 60 years, a metabolic workup should be performed. The following metabolic conditions have definite associations with CPPD [12] :

  • Hemochromatosis
  • Hyperparathyroidism
  • Hypophosphatasia [12]  

Hypothyroidism has a probable association with CPPD, so thyroid function testing should be included in the metabolic workup. [23]


Lab Studies

General laboratory studies usually are not helpful in calcium pyrophosphate deposition (CPPD) disease. The white blood cell (WBC) count and erythrocyte sedimentation rate (ESR) may be elevated.

Evaluating for an underlying metabolic disease (eg, hemochromatosis, hyperparathyroidism, hypothyroidism) is reasonable, especially in younger patients. Hypomagnesemia—and even low-normal serum magnesium levels—has been associated with a higher prevalence of knee chondrocalcinosis. [24] Laboratory tests can include the following:

  • Serum calcium, phosphorus, magnesium, and alkaline phosphatase levels
  • Iron level, total iron-binding capacity, transferrin saturation, and ferritin level
  • Thyroid-stimulating hormone and free thyroxine levels


Occasionally, pseudogout may present as a pseudoseptic syndrome with acute arthritis, fever, and leukocytosis with a left shift.

The diagnosis of acute pseudogout is made by performing compensated polarized microscopy after aspiration of fluid from the involved joint. The most commonly involved joint is the knee, followed by the wrist, the MCP joints, the elbows, and the MTP joints. Centrifugation of the synovial fluid sample may improve identification of calcium pyrophosphate crystals. [25]

The crystals are rhomboid-shaped, weakly positively birefringent, and difficult to see. If intracellular, an acute attack of pseudogout is strongly suggested. Aspiration of the fluid from affected joints during an acute attack usually yields mildly to moderately inflammatory fluid, with 10,000-50,000 WBCs/µL, more than 90% of which are neutrophils. (See the images below.)

Calcium pyrophosphate deposition disease. Appearan Calcium pyrophosphate deposition disease. Appearance of calcium pyrophosphate dihydrate crystals obtained from the knee of a patient with pseudogout. The crystals are rhomboid-shaped with weakly positive birefringence, as seen by compensated polarized microscopy. The black arrow indicates the direction of the compensator.
Calcium pyrophosphate deposition disease. High-pow Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The black arrow indicates the direction of the compensator. Crystals parallel to the compensator are blue, while those perpendicular to the compensator are yellow.
Calcium pyrophosphate deposition disease. High-pow Calcium pyrophosphate deposition disease. High-powered view of calcium pyrophosphate dihydrate crystals with compensated polarized microscopy. The crystals parallel to the compensator were blue, while those perpendicular to the compensator were yellow. However, the crystals have been rotated 90%, resulting in a color change in both of them. The direction of the compensator was not changed and is indicated by the black arrow.

Gout and pseudogout can coexist, even in the same joint; therefore, the presence of gout does not rule out the possibility of pseudogout and vice versa. Ultrasonography may be helpful in diagnosing pseudogout. (See the image below.)

Calcium pyrophosphate deposition disease. Ultrason Calcium pyrophosphate deposition disease. Ultrasonography of the wrist demonstrates chondrocalcinosis.

Pseudorheumatoid arthritis

The erythrocyte sedimentation rate (ESR) is usually elevated in pseudorheumatoid arthritis. The older age at onset for this condition, the absence of rheumatoid factor, and the presence of chondrocalcinosis help to differentiate it from true rheumatoid arthritis. However, rheumatoid arthritis can occur in older individuals. In addition, older individuals may have low-titer–positive rheumatoid factor. Thus, the diagnosis must be made with care.


Imaging Studies

Radiography is the criterion diagnostic standard for imaging of CPPD. However, ultrasonography appears more useful for detection of chondrocalcinosis (cartilage calcification, most commonly due to CPPD). [26] For complete discussion of imaging techniques, see Imaging in Calcium Pyrophosphate Deposition Disease.


Radiologic studies usually include the hands, wrists, pelvis, and knees (see the images below). The pelvic radiograph should include an anteroposterior view that shows the symphysis pubis and hips.

Calcium pyrophosphate deposition disease. Radiogra Calcium pyrophosphate deposition disease. Radiograph of the knee showing chondrocalcinosis involving the meniscal cartilage, as well as evidence of osteoarthritis.
Calcium pyrophosphate deposition disease. Radiogra Calcium pyrophosphate deposition disease. Radiograph of the wrist and hand showing chondrocalcinosis of the articular disc of the wrist and atypical osteoarthritis involving the metacarpophalangeal joints in a patient with underlying hemochromatosis.

CPPD may involve hyaline cartilages, fibrocartilages, or tendons. [27] Chondrocalcinosis is usually found in the articular cartilage or meniscal cartilage of the knee, the triangular ligament of the wrist, the symphysis pubis, or the glenoid or acetabulum labra. [27] Chondrocalcinosis has also been noted in other areas of the wrist (aside from the fibrocartilage), such as the distal radioulnar joint and the midcarpal joint, as well as in the pisotriquetral joint. In addition, it has been reported in the spine as calcification of the ligamentum flavum. [28]

In some situations, hemochromatosis can produce specific radiographic findings, such as large, hooklike osteophytes, especially around the second to fifth MCP joints. However, these findings also can occur in patients with CPPD alone.

Hooklike osteophytes are a common radiologic finding in patients with a pseudo-osteoarthritis condition and are usually present along the second and third metacarpal heads.

Radiologically, erosions can be observed in pseudorheumatoid arthritis but are usually associated with chondrocalcinosis.

MRI and ultrasonography

Routine magnetic resonance imaging (MRI) has not been shown to be as sensitive as radiography in detecting the presence of CPPD. However, 4T MRI holds better promise in detecting these crystals.

Ultrasonography (US) has been significantly beneficial in the visualization of CPPD crystals. [29] In addition, Gutierrez et al reported that US is accurate and reliable for detecting articular cartilage calcification at the knee level in patients with CPPD. In their study, US detected hyaline cartilage spots in at least one knee in 44 of 74 patients with CPPD (59.5%), whereas radiography detected hyaline cartilage spots in 34 of those patients (45.9%) (P < 0.001). [30]

A systematic review concluded that US is potentially a useful tool for the diagnosis of CPPD. However, the accuracy of US varied widely, depending on the reference standards used, and these authors suggest that universally accepted definitions are necessary in order to assess the role of US in the diagnostic process. [31] These findings were also reported in the American College of Radiology Appropriateness Criteria for evaluation of suspected inflammatory arthritis. [32]

Further evidence supporting the use of US in the detection of CPPD comes from a study by Forein et al that compared US and radiography of the wrist for diagnosis of CPPD disease. In their study of 32 patients with CPPD disease and 26 controls, US had sensitivity of 94% and specificity of 85%, while the sensitivity and specificity of radiography were 53.1% and 100%, respectively. [33]

Filippou et al demonstrated that US was as accurate as synovial fluid analysis for the diagnosis of CPPD disease in 42 patients with primary knee osteoarthritis waiting to undergo knee replacement surgery. In this study, cartilage histology was used as the reference standard. US had 96% sensitivity and 87% specificity; radiography, 75% sensitivity, and 93% specificity, while synovial fluid analysis had 77% sensitivity and 100% specificity. [34]

A study by Cipolletta et al supports the diagnostic accuracy of US in evaluating wrist involvement in CPPD. Evaluation of 200 wrists, in 61 patients and 39 controls, using both conventional radiography and US, showed that US had sensitivity of 0.95 (0.86-0.99), specificity of 0.85 (0.69-0.94), and diagnostic accuracy of  0.91 (0.84-0.96); comparable figures for conventional radiography were 72 (0.59-0.83), 1.0 (0.91-1.0), and 0.83 (0.74-0.90), respectively. [35]

Further US data show that scanning a higher number of sites with demonstration of hyperechoic spots that do not generate acoustic shadowing in the hyaline and fibrocartilage can increase the specificity for CPPD. Real-time images can be reviewed during office visits to help illustrate CPPD, which may facilitate patient education. [36]

Diagnosing CPPD with US typically requires scanning multiple joints to localize the crystals. The 2 most commonly affected sites where these crystals can be seen are the triangular fibrocartilage complex (TFCC) of the wrist and the knee. US at these sites show thin hyperechoic bands parallel to the surface of the hyaline cartilage. Other findings include a punctate pattern consisting of several hyperechoic spots and homogeneous hyperechoic nodular or oval deposits in the articular surface. (See the image below.) These homogeneous structures are referred to as double contour. Double contour is also noted in gout, but in CPPD disease the crystal is more moveable with dynamic imaging than it is in gout. [37]

Calcium pyrophosphate deposition disease. Ultrasou Calcium pyrophosphate deposition disease. Ultrasound scan of the triangular fibrocartilage complex (TFCC) of the wrist shows thin hyperechoic bands parallel to the surface of the hyaline cartilage. Other findings include a punctate pattern consisting of several hyperechoic spots and homogeneous hyperechoic nodular or oval deposits in the articular surface.