| disease | Hydroxyapatite Deposition Abdominal Mass Disease |
Hydroxyapatite (calcium hydroxyapatite, HA) is the primary mineral salt in bones (including teeth). Its deposition in tissues outside of bones and teeth is known as ectopic calcification. Ectopic calcification can occur in various parts of the body, including local and systemic connective tissues, joints, and periarticular tissues. Calcification in joints and periarticular tissues often does not present symptoms, but it can sometimes lead to acute arthritis and various other chronic joint disorders. The condition generally has mild symptoms or may even be asymptomatic, but it can also cause joint destruction and deformity, necessitating joint replacement surgery. Periarticular deposition of HA can occur at any age, but its intra-articular deposition is more commonly seen in the elderly.
bubble_chart Etiology
The cause of HA deposition is unclear. Normal connective tissue contains calcification-inhibiting factors. In vitro experiments have shown that inorganic pyrophosphate, proteoglycan aggregates, and non-collagenous proteins all have the effect of preventing tissue calcification. If the normal calcification inhibition is weakened due to tissue trauma, aging; or if nucleating agents are present within the tissue, promoting cellular calcification mechanisms; or if metabolic disorders lead to an increase in local solute concentration, all these can promote abnormal deposition of calcium salts[21].
According to current clinical observations, abnormal HA deposition can generally occur in the following three situations[20]:
1. Tissue injury (dystrophic calcification);
2. Hypercalcemia or hyperparathyroidism (metastatic calcification);
3. Idiopathic calcification of unknown cause.
HA deposition often occurs in joints prone to injury, relatively ischemic tendons, diseased tissues (local or systemic connective tissue diseases) or lesions, and elderly patients, indicating that normal tissue is important in preventing calcification. Metabolic disorders, hypercalcemia, hyperphosphatemia, hyperparathyroidism, vitamin D intoxication, diabetes, and chronic renal failure can all promote calcification, indicating that metabolic factors play a role. In patients with idiopathic calcification, there is no obvious cause. Moreover, such patients often have multiple sites and joints involved, with other crystalline components often mixed in the deposits, large deposits, or a family history, suggesting that these patients have systemic calcification-promoting factors.bubble_chart Pathological Changes
HA monomers are small, rod-shaped or needle-shaped crystals, ranging in length from 50 to 500 Å, and are non-birefringent. They can only be observed under an electron microscope. These crystals can aggregate into complexes, found both intracellularly and extracellularly, measuring 1 to 20 μm in length, spherical in shape, staining faintly purple with Wright stain and bright red with alizarin red.
The deposits are dispersed within the joint as monomeric crystals or small aggregates, but can form large "massive" deposits around the joint. Over time, these deposits can grow larger and may develop in a tumor-like manner [22, 23].
HA deposits in the joint and periarticular tissues generally do not cause symptoms, but when the crystals are released, they can trigger acute inflammation, manifesting as synovitis or periarthritis [20, 21].
HA deposits are also observed in chronic joint diseases such as osteoarthritis and destructive arthropathy. According to observations, HA deposition is not a result of osteoarthritis but rather a cause of joint disease. This is because: (1) primary osteoarthritis rarely occurs in the joint; (2) high levels of collagenase, proteases, and collagen fragments, exceeding those found in rheumatoid arthritis and uncomplicated osteoarthritis, have been detected in the non-inflammatory synovial fluid of severe HA arthropathy; (3) HA crystals have been isolated in young individuals (<30 years old) without osteoarthritis. Experimental evidence shows that synovial tissue culture, when exposed to HA crystals, significantly increases the release of collagenase and proteases. Therefore, HA deposition in joints may lead to destructive changes in the joint.
bubble_chart Clinical Manifestations
1. Periarthritis can occur at any age and in any gender. It often begins suddenly after injury or spontaneously, with significant pain and local tenderness. Symptoms gradually alleviate or completely subside within a few days. The shoulder joint is involved in 70% of cases. The condition affects the subacromial bursa and tendons, leading to restricted movement, and the local skin may become red and swollen. Other commonly affected joints include the knee, hip, wrist, and finger joints. Sometimes, chronic arthralgia occurs, and joint movement often involves the affected tendons, causing pain.
2. Synovitis Acute synovitis can involve multiple joints. Sometimes, apart from finding HA crystals in the inflammatory synovial fluid, there are no other obvious causes. The cell count in synovial fluid is usually below 2×109/L (2000/mm3), but can sometimes be as high as 50×109/L (50000/mm3), predominantly mononuclear cells, with occasional predominance of neutrophils.
3. Osteoarthritis The joint manifestations resemble primary osteoarthritis, but the affected joints differ. HA crystals can be found in the synovial fluid, synovial tissue, and cartilage. Whether these crystals are the cause or the result of joint pathology remains debated among authors. However, as mentioned earlier, HA crystals can cause inflammation and directly injure the joint.
4. Destructive arthropathy This is more common in the knee and shoulder joints, presenting with pain, swelling, and restricted movement. It mostly occurs in elderly patients. Symptoms can range from mild to severe pain, from joint dysfunction to joint erosion, atrophy, destruction, and deformity. The joint fluid cell count is less than 1×109
bubble_chart Auxiliary Examination
The cell count in synovial fluid is generally not high. In chronic joint diseases, the cell count is often below 1×109/L, and in acute or subacute cases, it is usually below 2×109/L, predominantly consisting of mononuclear cells.
X-ray examination generally has no special diagnostic value. However, severe joint lesions show erosion, destruction, and proliferative changes, and small calcified deposits cannot be displayed on X-ray images. Large crystalline aggregates appear as calcified shadows on X-ray films. At the tendon-muscle attachment sites around the joint, spherical or irregular calcified shadows are present, lacking trabecular bone structure and not showing the "linear" appearance seen in calcium pyrophosphate dihydrate crystal deposition disease. These calcified shadows can undergo dynamic changes during acute arthritis, initially appearing as clear and distinct shadows, then becoming soft and diffuse, and gradually disappearing. This is presumably due to the outflow and phagocytosis of crystals.
HA deposits in synovial fluid and synovial tissue can first be screened with alizarin red staining to observe if there are red spherical calcium-containing substances. Light microscopy can only reveal aggregated spherical HA crystals, while individual crystals require electron microscopy for identification.
In clinical practice, for patients suspected of having hydroxyapatite deposition disease, an X-ray plain film examination can be initially performed, followed by taking synovial fluid for alizarin red staining under light microscopy, and selecting appropriate specimens for electron microscopy [21] to make a clinical diagnosis. Precise crystal identification relies on electron diffraction, X-ray diffraction, or infrared spectroscopy [20]. This disease can present with HA deposits in and around the joints, with acute or chronic injuries occurring in the joint capsule, tendons, bursae, or articular surfaces. It most commonly occurs in overused joints. X-ray examination generally lacks diagnostic value, and a definitive diagnosis still depends on the identification of HA crystals.
bubble_chart Treatment Measures
For acute inflammation, symptomatic treatment involves taking non-steroidal anti-inflammatory drugs. In cases of acute synovitis, aspirating joint effusion or intra-articular injection of glucocorticoids can shorten the course of the disease and alleviate symptoms. For those with chronic and severe joint destructive changes, medication is ineffective, and surgical removal of HA deposits may sometimes be necessary.
