Pseudogout (Calcium Phyrophosphate Deposition Disease)

Are You Confident of the Diagnosis?

Pseudogout refers to the clinical entity of acute joint inflammation that occurs because of an inflammatory response to deposited calcium-containing crystals. The term chondrocalcinosis refers to deposition of these crystals within the articular cartilage (Figure 1). The most common crystal causing this is calcium pyrophosphate dihydrate (CPPD). Most joints that have chondrocalcinosis remain asymptomatic. Chondrocalcinosis is routinely detected by plain radiography, most often as an incidental finding. While calcium crystals are necessary for an attack of pseudogout to occur, some joints with pseudogout may lack enough chondrocalcinosis be detectable on plain radiographs.

Figure 1.

• What you should be alert for in the history

By far the most common presentation of CPPD deposition disease (CPPDD) is acute monoarthritis resembling gout. In fact, the patient may have been erroneously diagnosed with gout (although there are a few patients with gout and pseudogout occurring simultaneously). The patient usually reports the sudden onset of severe pain and swelling of the affected joint. There may or may not be a history of minor trauma or overuse. Frequently, there is a history of pre-existing osteoarthritis.

By far the most commonly affected joint is the knee, followed by the shoulder, hip and the wrist. Occasionally attacks can be polyarticular. Pseudogout patients are older on average at the time of their first attack than gout patients. As with gout, pseudogout has a propensity to attack patients when they are ill or hospitalized for an unrelated reason.

Patient demographics can be helpful to distinguish between the two conditions. For example, a female octogenarian who is hospitalized for pneumonia and who suddenly develops inflammation of one knee (without a previous history of podagra) is overwhelmingly more likely to have pseudogout than gout. As in the case with gout, polyarticular attacks occur with signs of systemic inflammation, but this is much less common than in gout. Patients with familial chondrocalcinosis will often present prior to age 40, sometimes as young as 20 years.

• Characteristic findings on physical examination

Because various aberrant genes have been associated with the phenotype of chondrocalcinosis, it follows that the clinical presentation vary among kindreds. Many persons are asymptomatic. If symptomatic, the most common pattern is sudden, severe monoarthritis, most commonly of the knee. Other common presentations include the pseudo-rheumatoid pattern and the pseudo-osteoarthritis pattern (Figure 2, Figure 3). Other tissues such as synovium, tendons and tendon sheaths can occasionally be infiltrated with CPPD (Figure 4, Figure 5).

Figure 2.

Figure 3.

Figure 4.

Figure 5.

A few persons will present with recurrent acute hemarthrosis or with a pseudo-neuropathic joint (Charcot joint) pattern. Some people present with either an acute or chronic carpal tunnel syndrome. Dialysis patients tend to develop a severe, destructive calcific arthropathy.

A small number of patients may develop tophaceous, soft tissue collections of CPPD, sometimes mixed with basic calcium phosphates (BCP). The most common area for this rare condition is in the vicinity of the temporomandibular joint. A firm mass is palpable in such cases and imaging studies often demonstrate erosion of the adjacent bone; this finding raises the suspicion of malignancy, which could result in more extensive surgery than is actually necessary. Simple excisional surgery is usually curative.

A potentially serious consequence of CPPDD is acute inflammation occurring at the level of C1-C2, the “crowned dens” syndrome. Approximately 70% of persons with chondrocalcinosis have calcific deposits at the level of the transverse ligament of C1 (Figure 6). The sudden onset of inflammation in or around these crystalline deposits can result in severe neck pain and possibly permanent neurological sequelae due to edema of the proximal spinal cord. This condition may be accompanied by fever and by meningeal signs on physical examination.

Figure 6.

One of the clues on physical examination is pain with head rotation, in contrast to those patients with simple spondylosis, in which there is normally pain only with bending of the spine. A few persons with the crowned dens syndrome have such voluminous calcific deposits in the region of C1-C2 that chronic cord compression occurs, even in the absence of acute inflammation. Some subacute cases have been reported to mimic polymyalgia rheumatica.

The clinical syndrome of pseudogout occurs when previously asymptomatic crystals trigger acute inflammation. Frequently the precipitant is a minor trauma that dislodges crystals from the cartilage surface into the synovial fluid where they trigger the inflammatory cascade. Within several hours the joint becomes warm and swollen and a large joint effusion develops.

CPPD and other calcium crystals can deposit asymptomatically within soft tissues until such time that inflammation is triggered, mimicking infectious cellulitis. If enough inflammation develops, the patient may exhibit fever, leukocytosis and dramatically elevated serum markers of inflammation. The classic pseudogout attack is self-limited, but tends to persist longer than the classic gout attack, often lasting several weeks.

• Expected results of diagnostic studies

Imaging

Chondrocalcinosis is typically detectable by plain radiography, although occasionally a patient may present with an attack of pseudogout without enough CPPD deposition in the cartilage to be visible on plain radiographs (Figure 1). Chondrocalcinosis is visible as a linear band of calcification within the substance of the articular cartilage. It is most readily detectable in radiographs of the knees, the wrists (particularly the triangular fibrocartilage on the ulnar aspect of the wrist) and the symphysis pubis.

Calcification is also readily detectable by computed tomography (CT) imaging, but is easily missed on magnetic resonance imaging (MRI), which tends to show calcium crystals as a signal void or as background density. For evaluation of the crowned dens syndrome, CT scanning is best for detecting the extent of calcification (Figure 6), while MRI scanning is best for detecting the degree of inflammation associated with the condition. Bone scintigraphy is the most sensitive imaging modality to detect the early inflammatory phase of heterotopic ossification.

Laboratory

Most persons with pseudogout or with chondrocalcinosis have normal laboratory findings. A serum calcium level that is elevated or near the upper limit of normal should raise the suspicion of hyperparathyroidism. Hypophosphatasia (a predisposing but rare condition for chondrocalcinosis) would be suggested by a low serum alkaline phosphatase level. There are usually no clues to hypomagnesemia, so it is worth obtaining a serum magnesium level in most chondrocalcinosis patients.

Patients younger than 60 years should be screened for hereditary hemochromatosis. If suspicion is high, or if there is a family history of hemochromatosis, the best screening consists of serum ferritin, serum transferrin saturation (approximated as serum iron divided by serum transferrin) and determination for the presence of the HFE gene (C282Y). Mildly elevated transaminases are nonspecific, but can be a clue to the presence of hemochromatosis. As mentioned previously, alkaline phosphatase may be elevated severalfold in acute heterotopic calcification, but will be normal in classic pseudogout patients.

Synovial fluid from the joint affected with pseudogout will typically be inflammatory (cell count >1000/mm3), appearing mildly to moderately cloudy. CPPD crystals are slightly rectangular or rhomboid in shape, compared to needle-like monosodium urate (MSU) crystals. They can usually (but not always) be distinguished by shape alone, without the aid of polarized light.

Under polarized light, CPPD crystals are only weakly birefringent while MSU crystals are strongly birefringent. Under compensated polarized light, CPPD crystals exhibit “positive” birefringence. In other words, a CPPD crystal will appear blue (a pale blue because CPPD crystals are only weakly birefringent) when the long axis of the crystal is aligned with the direction of slow vibration of the compensating filter, and yellow when the crystal is perpendicular to this direction. Occasionally CPPD crystals may be so weakly birefringent as to appear non-birefringent. MSU crystals on the other hand exhibit strong “negative” birefringence. They are bright yellow when aligned parallel to the axis of slow vibration of the compensating filter, and bright blue when perpendicular to this axis.

Hydroxyapatite crystals are non-birefringent. They have no brightness under polarized light, and no color under compensated polarized light. The shape of hydroxyapatite crystals is chunk-like under the light microscope. They have no visible regularity of shape. Without special staining they cannot be reliably distinguished from intracellular granules or from extracellular debris. Alizarin red stain is used to identify calcium-containing crystals under ordinary light (Figure 7). Hydroxyapatite crystals stain bright orange-red while CPPD crystals stain less intensely. MSU crystals are not stained by alizarin red.

Figure 7.

• Diagnosis confirmation

The pseudo-rheumatoid pattern of CPPDD clinically resembles rheumatoid arthritis with polyarticular involvement, often with morning stiffness and chronic joint inflammation. Radiographically this entity lacks the classic features of rheumatoid arthritis. Chondrocalcinosis is usually evident. Arthrocentesis will show typical intracellular CPPD crystals. Rheumatoid factor and anti-CCP antibodies (anti-cyclic citrullinated protein) are typically negative.

The pseudo-osteoarthritis pattern is much more common. The pattern is one of “inflammatory osteoarthritis” or “erosive osteoarthritis” (Figure 3). While superficially this can also resemble rheumatoid arthritis, the pattern of joint involvement is more typical of osteoarthritis. Principally involved are the knees, the wrists (particularly the first carpometacarpal joints), other large joints including the hips and shoulders, and frequently the distal interphalangeal (DIP) joints. Some persons have prominent degenerative spinal involvement as well, with variable degrees of annular calcification, facet involvement and bony overgrowth, sometimes resembling diffuse idiopathic skeletal hyperostosis (DISH).

If the MCP joints are significantly involved along with the wrists, this disease may be confused with rheumatoid arthritis. This is frequently a painful disease with relentless, severe degenerative changes and with variable degrees of chronic and acute inflammation, accelerated joint destruction and unusually aggressive radiographic changes. In fact, as the disease progresses and cartilage degenerates, the chondrocalcinosis becomes more difficult to see on radiographs. In such a case, the diagnosis of CPPDD may be missed (Figure 3).

There are three serious but treatable underlying conditions that should always be considered when making a diagnosis of pseudogout. These are hyperparathyroidism, hemochromatosis and hypomagnesemia. Hemochromatosis has been called “the bronze diabetes.” Associated findings may include skin hyperpigmentation, glucose intolerance, cardiac conduction defects or cardiomyopathy; the associated arthritis can resemble either rheumatoid arthritis or osteoarthritis, characteristically affecting the second and third metacarpophalangeal (MCP) joints of the hands.

There are no specific dermatologic manifestations of CPPDD. As noted above, prominent soft tissue inflammation will occasionally accompany pseudogout, particularly if inflammation proceeds within tendon sheaths.

In contrast to CPPDD, calcification and inflammation of the skin and soft tissues is more commonly associated with the basic calcium phosphates (BCP), usually those of the apatite family. Hydroxyapatite is the best-known of this family because of its importance in teeth and in bones. In the region of joints, apatites are best known for their role in acute calcific bursitis or acute calcific tendinitis. Local inflammation can be so acute and severe as to mimic septic arthritis or cellulitis (Figure 8), but is ultimately self-limited over days or weeks. The usual precipitant appears to be minor trauma or overuse, but frequently there is no obvious precipitating factor.

Figure 8.

Apatite deposition is visible on plain radiographs as an amorphous “cloud” of calcification adjacent to a joint. The calcification is typically outside the joint proper, giving rise to prominent soft tissue inflammation with a relatively small, noninflammatory synovial effusion. This is in contrast to the classic synovial fluid findings in gout or in pseudogout. Radiographs of other joints and tendons of the same patient will frequently show other, asymptomatic areas of apatite deposition, suggesting that most apatite deposition occurs silently, as is the case with CPPDD.

Apatite deposition is much more likely to come to the attention of the dermatologist than is CPPD. For instance, cutaneous apatite deposition is frequently seen in both scleroderma and in dermatomyositis, particularly in the childhood form of dermatomyositis (Figure 9, Figure 10. Figure 11). If deposits become large, or if trauma or ischemia occurs, the deposits may drain a white, pasty material. If ulcerations occur on the digital tips, as is often the case in scleroderma, granular apatite may drain; such lesions may require months for complete healing. Microscopic examination of the exuded material allows rapid differentiation from both monosodium urate (MSU) and CPPD. Apatite crystals are small, amorphous, chunk-like crystals that exhibit either little or no birefringence under polarized light (depending on the exact chemical composition).

Figure 9.

Figure 10.

Figure 11.

Some persons exhibit a familial tendency to form deposits of apatite at sites of minor, repetitive trauma. Figure 12 shows an extreme example of calcific pre-patellar bursitis (“housemaid’s knee”).

Figure 12.

Hydroxyapatite is the main crystal involved in heterotopic ossification. This is a painful, inflammatory condition that occurs for unknown reasons in some persons following joint surgery or following paralysis, as from a cerebrovascular accident, or more commonly following spinal cord injury. Hydroxyapatite is deposited in the soft tissues, and if left untreated it may result in ankylosis of the affected joint. In muscle, progressive ossification of the hydroxyapatite deposits may ultimately lead to myositis ossificans (Figure 13). The fever and the signs of local inflammation can be of such intensity that this entity may be mistaken for septic arthritis, cellulitis or osteomyelitis. If inflammation and calcification are superficial enough to affect the skin, ulceration and post-inflammatory hyperpigmentation may occur (Figure 14).

Figure 13.

Figure 14.

Heterotopic ossification is a particularly serious problem if it occurs following hip replacement surgery. Clinically significant heterotopic ossification occurs in 2-7% of hip replacements. It often presents as the sudden onset of pain several weeks (3-12 weeks) after total joint arthroplasty, raising the suspicion of prosthetic joint infection. Bone scintigraphy (Figure 15) and CT scan are helpful for the diagnosis. Tagged leukocyte scanning may assist in excluding infection. Magnetic resonance imaging may be misleading due to the inability of this modality to adequately visualize calcium deposits. Alkaline phosphatase is frequently elevated severalfold, which offers a clue to the diagnosis.

Figure 15.

Apatite deposition is also associated with a destructive form of osteoarthritis of the shoulder known as Milwaukee shoulder, occurring principally in elderly females. The primary event in such cases appears to be a complete rotator cuff tear that destabilizes the glenohumeral joint, leading to excessive wear of the glenohumeral joint in persons who are believed to be predisposed to osteoarthritis. In this condition, large noninflammatory joint effusions occur, often with free hydroxyapatite crystals in the fluid, but with scant white cells. Nevertheless, the condition is very painful and debilitating and normally requires joint replacement surgery for significant relief.

Calciphylaxis is a particularly virulent form of cutaneous calcification and necrosis. It is most frequently associated with end-stage renal disease or dialysis, although the presence of an underlying connective tissue disease such as lupus or dermatomyositis has been identified as a risk factor for this condition.

Who is at Risk for Developing this Disease?

Chondrocalcinosis is a necessary prerequisite for the development of pseudogout, yet it is quite common to diagnose pseudogout in persons who have no prior knowledge of their chondrocalcinosis. The risk of chondrocalcinosis increases with age. Approximately 40% of octogenarians will have (usually asymptomatic) chondrocalcinosis.

When one considers how common chondrocalcinosis is, one wonders why pseudogout is not more common. Most persons with chondrocalcinosis will never have an attack of pseudogout. A history of trauma to a joint (or even prior arthroscopy) can accelerate the formation of chondrocalcinosis, resulting in an unexpected and unwelcome attack of pseudogout several years later.

A number of conditions are associated with the development of chondrocalcinosis. These include hemochromatosis, hyperparathyroidism, hypomagnesemia, and hypophosphatasia. While there are many causes of hypomagnesemia, those most closely associated with chondrocalcinosis are the Bartter syndrome (hypomagnesemia, hypokalemia and metabolic alkalosis) and Gitelman’s syndrome (hypomagnesemia, tubular hypokalemia and hypocalciuria).

There has been speculation that hypomagnesemia induced by diuretic use in the elderly could play a role, but so far there are no adequate studies to support this. One condition common to these conditions is an excess of cartilage-bound pyrophosphate. Chondrocalcinosis is also associated with a number of rare conditions including Wilson disease, and ochronosis. There are rare reports of tacrolimus triggering soft tissue calcification.

In the past decade a number of enzyme defects have been associated with chondrocalcinosis. For example, hereditary hypophosphatasia is due to missense mutations of the ectoenzyme tissue-nonspecific alkaline phosphatase (TNAP). It is believed that families with chondrocalcinosis are heterogeneous with respect to the genetic defects involved. Several mutations in the ankylosis human (ANKH) gene have been recently described in some kindreds. This gene codes for what has been described by Zaka and Williams as a multipass transmembrane protein that regulates the transport of inorganic pyrophosphate, and which may affect several key enzymes.

An aberrant gene on the long arm of chromosome 8 is responsible for a particularly severe form of chondrocalcinosis with destructive osteoarthritis while other mutations on the short arm of chromosome 5 are associated with different phenotypes in other families. The specific enzymes that are thought to play critical roles in the process of calcification are being targeted for genetic studies. The few mutations identified so far do not seem to explain the vast majority of sporadic cases of chondrocalcinosis.

There is also a large group of familial chondrocalcinosis patients in whom the underlying metabolic defect is unknown. In some kindreds, chondrocalcinosis is associated with other inborn musculoskeletal defects such as spondyloepiphyseal dysplasia, brachydactyly and premature degenerative joint disease. Some familial cases are associated with diffuse idiopathic skeletal hyperostosis (DISH). A family with CPPDD and familial hpocalciuric hypercalcemia has been described by Volpe and colleagues. In the past it was thought that hypothyroidism was also associated with chondrocalcinosis, but this association has not been borne out in more recent rigorous studies, although there may be an association with flagrant myxedema.

CPPD is frequently associated with deposition of basic calcium phosphates (BCP) in close proximity. This is perhaps best illustrated in the case of Milwaukee shoulder and the pseudo-osteoarthritis pattern of CPPDD. BCP alone has been reported to cause chondrocalcinosis, including familial types.

What is the Cause of the Disease?

In addition to the presence of calcium crystals within cartilage, the other necessary ingredient is phagocytosis of crystals by inflammatory cells, usually neutrophils. It is only then that the chondrocalcinosis becomes symptomatic.

Systemic Implications and Complications

Given that some underlying causes of chondrocalcinosis are treatable, it is most important to evaluate younger persons (particularly those <60 years of age) who present with chondrocalcinosis or with pseudogout. The main underlying conditions that should be sought in such individuals include hemochromatosis, hyperparathyroidism, and hypomagnesemia. Evaluation would include two serum calcium levels (or one serum calcium and a parathyroid hormone [PTH] determination), a serum magnesium level and either a serum iron/transferrin ratio or a serum ferritin level. As a rule, patients older than 70 years of age do not require evaluation (with the exception of serum calcium) unless there are obvious signs of a predisposing condition.

Most cases of pseudogout are idiopathic, especially in the elderly. The three most important systemic underlying conditions that should be sought are hyperparathyroidism, hemochromatosis and hypomagnesemia. Fortunately, screening for these three entities is relatively straightforward.

If hypomagnesemia is discovered, then further evaluation will be needed to determine an etiology. Causes of hypomagnesemia associated with CPPD include the Bartter syndrome (hypomagnesemia, hypokalemia and metabolic alkalosis) and Gitelman’s syndrome (hypomagnesemia, tubular hypokalemia and hypocalciuria). Other common causes include diuretic use, diarrhea, inadequate intake, ethanol abuse, hypercalcemic states, short bowel syndrome, and medications such as cyclosporine, aminoglycosides, amphotericin, pentamidine and others. However, most of these have not been associated with CPPDD.

Rarely, cases of chondrocalcinosis are associated with ochronosis, Wilson disease and hypophosphatasia. Ochronosis and Wilson disease have additional physical findings that can be sought easily. For instance, simple transillumination of the pinna of the ear is a reasonable screening test for ochronosis. Wilson disease is rare after age 40. Sometimes a Kayser-Fleischer ring is visible on simple inspection, and a serum ceruloplasmin is a useful screening test. Hypophosphatasia is easily screened for using a complete metabolic panel.

Familial forms of chondrocalcinosis are frequently associated with varying degrees of osteoarthritis of a large joint, small joints, and/or the spine, depending upon the kindred affected. Hemochromatosis is sometimes called “the bronze diabetes.” Associated findings may include skin hyperpigmentation, glucose intolerance, cardiac conduction defects or cardiomyopathy; the associated arthritis may resemble either rheumatoid arthritis or osteoarthritis.

Unfortunately, treatment of underlying conditions does not reverse or prevent joint damage, and pseudogout attacks tend to continue. Attacks of pseudogout may increase in frequency following parathyroid surgery. There is no effective treatment for the osteoarthritis associated with chondrocalcinosis. There is some evidence that as a group, patients with chondrocalcinosis are prone to faster progression of osteoarthritis.

Treatment Options

Treatment options are summarized in Table I. Preventive measures against attacks are listed in Table II.

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