| disease | Calcium Pyrophosphate Dihydrate Deposition Disease |
| alias | Pyrophosphate Arthropathy, Chondrocalcinosis, Fake Pain Wind, CPPD |
Calcium pyrophosphate dihydrate deposition disease (CPPD) has been discovered for over 30 years. Before the confirmation of CPPD crystals, it was often referred to as "pain wind." Later, it was also called "pseudogout." Due to its manifestation of articular cartilage calcification on X-rays, it was also termed "chondrocalcinosis." However, this disease may not present with cartilage calcification, so it is now commonly referred to as "pyrophosphate arthropathy" [9].
bubble_chart Epidemiology
This disease has a high incidence rate in the elderly philtrum. According to autopsy investigations, approximately 6% of individuals around 72 years old have calcium pyrophosphate crystal deposits in their joints. X-ray examinations reveal that nearly 50% of people around 90 years old show signs of cartilage calcification, though most exhibit no clinical symptoms. About half of those with clinical symptoms present with heroic pain wind symptoms[10,11]. The incidence rate between men and women is approximately 1.4:1, showing no significant difference[12].
In 1988, McCarty[10] classified it into multiple types (Table 37-1), indicating that the disease is associated with various factors. These include hereditary and non-hereditary types, as well as those related to metabolic disorders and joint trauma. According to relevant statistics, over 80% of patients are aged 60 or older; 70% of patients have a history of joint injury; and most young patients (<50 years old) are accompanied by metabolic disorders[13].
Table 37-1 Classification of Pyrophosphate Arthropathy
| 1. Hereditary |
| 2. Sporadic (Idiopathic) |
| 3. Associated with Metabolic Diseases Hyperparathyroidism, familial hypocalciuric hypercalcemia, hemochromatosis, hemosiderosis, hypothyroidism, pain wind, hypomagnesemia, hypophosphatemia, amyloidosis. |
| 4. Associated with Joint Trauma or Surgery |
The mechanism of CPPD crystal deposition remains unclear. Most theories suggest it is related to increased local inorganic pyrophosphate (PPi) levels and weakened inhibitory effects of cartilage glycoproteins on PPi deposition. Under normal conditions, nucleoside triphosphate (NTP) is broken down by nucleoside triphosphate pyrophosphohydrolase (NTPPPase) into nucleoside monophosphate (NMP) and PPi, which is then further degraded by inorganic pyrophosphatase (PPiase) into inorganic phosphate (Pi).
If the activity of NTPPPase increases while PPiase activity decreases, coupled with weakened local tissue inhibitory effects on deposition, it can lead to the accumulation of inorganic pyrophosphate. It is reported that with aging or tissue injury, the inhibitory effect on deposition gradually diminishes. Therefore, CPPD deposition is more common in the elderly and increases with age; it is also observed at sites of tissue injury, explaining the higher incidence in knee joints. Metabolic disorders can also alter the physicochemical properties of local tissues, favoring CPPD crystal deposition. For example, in hemochromatosis, iron ions directly alter cartilage properties while also inhibiting PPiase, thereby promoting CPPD deposition [13]. Whether these hypotheses fully explain the mechanism of CPPD deposition remains uncertain [10]. However, recent studies have shown that in patients with CPPD deposition disease, the ATP concentration in joint fluid is higher compared to other forms of arthritis [14]. ATP can be hydrolyzed by NTPPPase into AMP and PPi; others have demonstrated that pyrophosphatase can dissolve calcium pyrophosphate [15]. This dissolution is stimulated by Mg++ and inhibited by Ca++. Fam also confirmed that in CPPD disease, joint fluid ATP levels are higher than in other forms of arthritis and correlate positively with PPi concentration.bubble_chart Clinical Manifestations
CPPD crystals deposit in tendons, ligaments, joint capsules, synovial membranes, and articular cartilage, mostly remaining asymptomatic and dormant. However, during "activity," they can manifest as acute inflammation or chronic degenerative changes. Inflammation and degeneration may occur sequentially or coexist, leading to diverse clinical presentations—acute, subacute, chronic, or intermittent episodes—making symptoms resemble those of various other joint diseases and complicating diagnosis.
1. Pseudogout About one-fourth of patients with pyrophosphate arthropathy exhibit pseudogout symptoms, with a higher prevalence in men. Joint inflammation often suddenly affects one or multiple joints, presenting as swelling and pain that resolves spontaneously within days. During remission, no symptoms are present. The entire inflammatory process closely resembles gout but differs in the following ways: ① **Joint involvement**: This condition most commonly affects large joints, with the knee being the most frequent (about half of cases), followed by the shoulder, elbow, wrist, ankle, and other synovial joints, including the first metatarsophalangeal joint. In contrast, true gout typically involves the first metatarsophalangeal joint, while large joint involvement is rare. ② **Pain characteristics**: In true gout, pain during inflammation is severe, whereas in this condition, pain is milder or "minor." Despite significant joint swelling, pain often subsides immediately after joint fluid aspiration. ③ **Inflammatory course**: True gout has a longer latency period in response to triggers (e.g., trauma, mercurial diuretics), taking days to develop redness and swelling. If tophi are present, they may ulcerate. In contrast, this condition reacts to triggers within hours, with pronounced joint swelling but less severe pain, a shorter inflammatory course, and no ulceration.
2. Pseudo-rheumatoid arthritis This type accounts for about 5% of CPPD patients, presenting as symmetric polyarticular involvement. Symptoms are milder but persist for weeks or months, including morning stiffness, fatigue, synovial thickening, flexion contractures, and elevated ESR. About 10% of patients test positive for IgM rheumatoid factor, and 1% closely mimic rheumatoid arthritis, often leading to misdiagnosis.
3. Pseudo-osteoarthritis This type manifests as progressive polyarticular degeneration, most commonly affecting the knees, followed by the wrists, metacarpophalangeal joints, hips, shoulders, elbows, and ankles. While overlapping with primary osteoarthritis in joint distribution (e.g., knees, hips), pyrophosphate arthropathy differs in sparing the distal and proximal interphalangeal joints (Heberden’s and Bouchard’s nodes) and the first carpometacarpal joint. CPPD arthropathy progresses symmetrically, but joints with severe trauma or fractures degenerate more severely. Flexion contractures are common, and knee valgus deformity often occurs.
4. Pseudo-neuropathic joint Pyrophosphate arthropathy can present as severe destructive joint disease, though neurological exams are usually normal. However, cases of grade I tabes dorsalis with Charcot’s knee and polyarticular CPP crystal deposition have been reported. An estimated 5% of CPPD patients develop tabetic neuropathic arthropathy.
5. Asymptomatic CPP crystal deposition On X-ray, the joints show CPP calcification but no clinical symptoms. Asymptomatic sexually transmitted disease cases account for 20% of total cases.
6. Others In some patients, particularly those with a family history, the spine may become straight and stiff, resembling ankylosing spondylitis. There have been reports of true bony ankylosis of the joints. Some patients, due to transient acute migratory arthritis attacks, are misdiagnosed as having "wind-dampness heat." Others, with milder episodes, are mistaken for "psychiatric symptoms," and so on.
Serum calcium and phosphorus are normal, alkaline phosphatase is normal.
The joint fluid is exudative and contains CPP crystals. During the acute inflammatory phase, these crystals are found within white blood cells; in the late stage of acute inflammation (third stage), they are present both intracellularly and extracellularly; during the chronic inflammatory phase, they are found outside white blood cells, appearing rod-shaped or resembling water caltrop base peel. When stained with alizarin red S, they show weak positivity and birefringence. The white blood cell count increases, ranging from several thousand to 100,000 cells per cubic millimeter, predominantly neutrophils. Synovial fluid should undergo bacterial staining and culture to rule out infectious inflammation. Sometimes the joint fluid appears bloody, which should not be simply attributed to traumatic hemarthrosis, as CPPD remains a possibility.
Since pyrophosphate arthropathy is often associated with certain metabolic disorders, routine tests should include serum magnesium, serum iron, ferritin, iron-binding capacity, uric acid, and thyroid function (TSH, T3, T4). If abnormalities are found, further investigations should be conducted.
Radiographic findings: Typical X-ray findings show punctate and linear radiodense shadows in the fibrocartilage or hyaline cartilage of the joint. When these shadows are typical and clear, they are diagnostic. However, if the changes are subtle or atypical, detailed X-rays of thinner areas (e.g., hands) and spot films of thicker areas (e.g., knees) should be taken. If early calcific deposits in the articular cartilage are seen on X-rays, further anteroposterior X-rays of both knees, hips, and the pubic symphysis, as well as posteroanterior views of both hands, should be performed. If no crystal deposits are found, chondrocalcinosis is unlikely. Antagonism: In joints with negative radiographic findings, CPP crystals may still be detected in the joint fluid, especially in cases with extensive joint space narrowing [10]. Differential diagnosis from gouty arthritis: Gout primarily manifests as small punctate lesions on the articular surfaces and bone ends, differing from the cartilage calcification seen in this condition [18]. When pseudoneuropathic arthropathy presents with Charcot-like joint changes, differentiation based solely on radiographic findings is insufficient. However, "true" Charcot joints are painless, whereas this condition is painful.
Calcific deposits can also occur in the joint capsule, ligaments, and tendons. Deposits in the synovial membrane can be large enough to mimic soft bone tumors [10]. These deposits may also exhibit tumor-like growth, with reports of tumor-like calcium pyrophosphate deposition in the fingers documented domestically [19].
1. Acute pseudogout is commonly seen in the elderly and often secondary to metabolic or endocrine diseases, such as diabetes, hyperparathyroidism, ochronosis, acromegaly, and hypophosphatemia. The triggering factors are similar to those of gout. The onset is acute, peaking within 12 to 36 hours. It usually manifests as monoarthritis or oligoarthritis, most frequently affecting the knee joint, followed by the ankle, wrist, elbow, and hip joints. The affected joints exhibit swelling, heat, pain, and dysfunction. X-ray examination reveals calcification of the articular cartilage, showing fine linear or punctate calcifications parallel to the subchondral bone surface. Synovial fluid analysis demonstrates calcium pyrophosphate crystals, which appear as rhomboid or brick-shaped particles of varying sizes under polarized light microscopy, exhibiting weak positive birefringence.
2. Chronic pseudogout often occurs secondary to osteoarthritis, caused by the continuous deposition of calcium pyrophosphate in degenerated cartilage within the joint cavity. X-ray examination shows osteoarthritic changes and cartilage calcification. The diagnosis is confirmed by the detection of calcium pyrophosphate crystals in synovial fluid.
bubble_chart Treatment Measures
Currently, it is not possible to remove the deposition of CPP in cartilage and joint capsules[13]. Treating related metabolic disorders does not lead to the reabsorption of already deposited CPP crystals[10]. Antagonism, certain treatments may interfere with calcium balance and trigger acute joint attacks, such as when parathyroidectomy or other treatments cause a rapid drop in blood calcium levels, which can induce pseudogout attacks[13]. Hypothyroidism, treated with thyroid hormone replacement, may also trigger symptom onset[10].
During the acute stage of an attack, symptomatic management can be performed. Nonsteroidal anti-inflammatory drugs (NSAIDs) used alone or combined with intra-articular corticosteroid injections, or joint fluid aspiration to relieve intra-articular pressure, can rapidly reduce inflammation. Intravenous colchicine is also effective for pseudogout, but oral administration is less effective for gout. For patients with chronic recurrent attacks, a low oral dose (1.2 mg daily) of colchicine can significantly reduce the frequency and duration of attacks[10].
During chronic intermittent periods, triggering factors such as trauma, surgery, forceful twisting, and prolonged walking should be avoided. All these actions or events can cause cartilage friction and microcrystal shedding, leading to acute arthritis attacks[13].
