Soft tissue calcification

Calcification of Soft tissue in Orthopedic practice, mechanism of calcification, Psommama bodied

1. Soft Tissue Calcification Vinod Naneria Girish Yeotikar Arjun Wadhwani Deptt of Orthopaedic Choithram Hospital & Research Centre, Indore, India

2. Why this topic? Ectopic calcification any where in the body has same pathophysiology. Most information on pathophysiology is gathered from the calcification of aortic valves, arterial calcification, and calcification in abnormal mineral balance as in CRF.

3. Definition Ectopic calcification is defined as inappropriate mineralization occurring in soft tissues. Ectopic calcifications are typically composed of calcium phosphate salts, hydroxyapatite, calcium oxalates and octacalcium phosphate.

4. Calcification - Types Metastatic calcification - systemic mineral imbalance is associated with widespread or metastatic ectopic calcification. Dystrophic calcification - In the absence of a systemic mineral imbalance, ectopic calcification is typically termed as dystrophic and it is localized.

5. Tissues in Dystrophic Degenerated or Dead Dystrophic mineralization is commonly observed in soft tissues as a result of injury, disease, and aging. Soft tissues commonly involved are skin, kidney, tendons, cardiovascular tissues and prosthetic devices appear particularly prone to developing this pathology.

6. Patho-physiology Calcification occurs due to the massive concentration gradient for calcium on the outside of the cell to the inside. Ca concentration inside the cell is a meager 10^-7 M, while it is 10^-3 outside the cell. Ca concentration is 1000 times higher on the outside of the cell than the inside.

7. Patho-physiology Inorganic phosphate has emerged as a major inducer of mineralization. Mineralization induced by inorganic phosphate dependent on the activity of the sodium‐dependent phosphate co-transporter, Pit‐1. Controlled, trans-cellular transport of Pi as a major requirement for matrix calcification.

8. Dystrophic Calcification There is activation of phosphatases during necrosis or severe cell damage. Ca2+ first binds to the phospholipid in damaged cell membranes promoting accumulation in cells, and then the phosphatases promote the reaction of phosphate with the Ca2+, producing calcium phosphate crystals. These calcium phosphate crystals then self-organize themselves to form a visible calcium microcrystals.

9. Patho-physiology - Osteopontin OPN, a secreted phosphoprotein, has emerged as a major inhibitor of ectopic mineralization. Osteopontin is a potent inhibitor of vascular cell calcification.  OPN treatment of biomaterials protected against ectopic mineralization. Osteopontin, inhibit apatite crystal initiation and growth. OPN stimulates resorption of ectopic calcification via peripheral macrophages and giant cells.

10. Dystrophic Calcification - Two steps Initiation or nucleation Phase in which precipitates of calcium phosphate begin to accumulate intracellularly in the mitochondria, Or extra-cellularly in the membrane-bound vesicles – matrix vesicles. Propagation Phase in which minerals deposited in the initiation phase are propagated to form mineral crystals.

11. Metastatic calcification Excessive mobilization of calcium from the bone Hyperparathyroidism Primary : parathyroid adenoma Secondary: parathyroid hyperplasia, CRF Bony destructive lesions Multiple myeloma, metastatic carcinoma, leukemia Prolonged immobilization Disuse atrophy of the bones and hypercalcemia

12. Excessive absorption of calcium from the gut Hyper- vitaminosis D Milk-alkali syndrome Excessive oral intake of calcium in the form of milk Administration of calcium carbonate for the treatment of peptic ulcer. Hypercalcaemia of Infency Sarcoidosis : macrophages activate a vitamin D precursor.

13. Summary Mineral balance and dead tissue – dystrophic Mineral imbalance and live tissue - metastatic

14. Mineral Balance - Dystrophic calcification Basically, this classification refers to whether or not the cell is alive. If the cell is dead, its Ca2+ pumps do not work and unable to maintain Calcium homeostasis. Massive flow of Ca2+ from outside the cell to inside occur. This type of calcification that occurs in dying tissues despite normal serum levels of Ca2+  .

15. Mineral Imbalance – Metastatic calcification  Serum concentration of Ca2+ levels is high. Concentration gradient favors Ca2+ influx into cells, and this causes an increase in Ca2+ concentration inside the cell. This type of calcification, where the cells are all alive, but the mineral balance is disturbed due to hypercalcemia.

16.  Psammoma bodies These Psammoma bodies are single necrotic cells that act as a single grain of sand from which a “pearl” of Calcium salts forms around it. The single necrotic cell is like a grain of sand among the other cells, Psammoma is in fact, Greek for sand. 

17. Metastatic Calcification Occurs in cell tissues whenever hypercalcemia is present throughout the body.  Hypercalcemia causes metastatic calcification, and also it can accentuate dystrophic calcification by increasing the concentration gradient for Ca2+ into the cell.

18. Causes of hypercalcemia Increase in secretion of PTH  (Parathyroid Hormone), which causes bone resorption and release of Ca2+ stored in bone into serum. This occurs in hyperparathyroidism and ectopic secretions of PTH related proteins by malignant tumors.  Resorption of Bone Tissue , that occurs secondary to primary bone marrow tumors (e.g. Multiple Myeloma, Leukemia, Osteosarcoma) or diffuse skeletal metastases (e.g. breast cancer), accelerated bone turnover (e.g. Paget’s Disease), or immobilization.  

19. Causes of Hypercalcemia Vitamin D related disorders , such as Vitamin D intoxication, Sarcoidosis (where macrophages activate a Vitamin D precursor), idiopathic hypercalcemia of infancy (Williams Syndrome, where the infant is very sensitive to Vitamin D). Renal Failure , which causes the retention of phosphate, and thus secondary hyperparathyroidism.

20. Tumoral calcinosis This is the painless deposition of calcium in peri-articular regions (around joints) of the body, just outside the joint capsules, as if a tumor is growing. It most commonly occurs in the shoulder joint, hip joint, and elbow joint. The etiology of this type of deposition of calcium is unknown, but it is believed to be as a result of hyperphosphatemia.

21. Chondrocalcinosis   Calcification occurs due to the accumulation of  calcium pyrophosphate  dihydrate  in connective tissues. [ Chondro -connective tissue, hence chondrocytes are connective tissue cells]. Its exact cause is unknown, although the breakdown of ATP, which produces pyrophosphate, is believed to be one possible cause. Hyperparathyroidism, hypothyroidism, hemochromatosis, hypophosphatemia and  hypomagnesia  are found to have a correlation with chondrocalcinosis.

22. Generic Differential Diagnosis of Dystrophic Soft Tissue Calcifications • Vascular venous insufficiency • Infection Parasitic infestation cysticercosis dracunculiasis • Neoplasm primary bone-forming tumor osteoma osteosarcoma tumor necrosis

23. Generic Differential Diagnosis of Dystrophic Soft Tissue Calcifications • Drugs Vitamin D • Autoimmune dermatomyositis scleroderma • Trauma heterotopic ossification injection granulomas

24. Dystrophic calcification in the Achilles tendon due to recurrent trauma and tendinitis.

25. Multiple bilateral phleboliths in the pelvic veins.

26. multiple “rice-grain” calcifications In cysticercosis .

27. Guinea worm calcification

28. Calcified Psoas abscess

29. skin atrophy over fingertips and calcinosis cutis .

30. Gluteal injection site calcification

31. Dermatomyositis soft tissue calcifications about the knee.

32. Heterotopic ossification post head injury

33. CPPD and chondrocalcinosis of hyaline articular cartilage and meniscal fibrocartilage of knee .