I should probably specify, for those of us who don’t watch Game of Thrones, the picture above is not calcification, it’s a fictional disease known as greyscale, where the skin turns hard and scaly, and thus dubbed in the fictional universe as being “turned into stone”.
This is basically how calcification works isn’t it? In fact, an official description of greyscale describes it as calcification of the skin that makes it appear as being converted to stone: and this is in essence what we will be talking about today, except of course, in more medical terms.
Calcification is the accumulation of calcium and calcium salts in body tissues. These calcium salts can be either calcium phosphate, calcium carbonate, or hydroxyapatite. I make Calcification sound pretty bad, but it does in fact have it’s uses. There is thus Physiologic Calcification and Pathologic Calcification.
This occurs when certain tissues harden due to the accumulation of calcium and calcium salts within them, as part of a normal, or maturative change. It occurs within areas in the body you definitely want to be strong and hard: osteoid in bones and enamel in teeth.
Evidence also exists to support that a very minimal amount of calcification occurs throughout the body due to aging. Because there is no pathology associated with this, they are also dubbed, physiologic. The most noteworthy of these aging related calcifications is normal/physiologic intracranial calcification. It should be noted that physiologic intracranial calcification can also occur as a result of a neurodegenerative disease, but usually the calcium itself does not contribute significantly to the progression of the neurodegenerative disease, and nor does it usually cause any extra disease itself if it accumulates in this way.
Intracranial calcification occurs within the skull, specifically, the brain and areas between the brain and skull. Intracranial calcification of the physiologic variety most commonly occurs in the following sites:
- Pineal Gland
- Seen in 2/3 of population and increases with age
- However, calcification under age 9 can suggest neoplasm
- Habenula (stalk of the pineal gland)
- Choroid Plexus
- Very common finding in the elderly
- Basal Ganglia
- Falx, dura mater or Tentorium Cerebelli
- Occurs in 10% of elderly and increases with age
- Petroclinoid Ligament
- Superior Sagittal Sinus
Pathologic Calcification is the abnormal deposition of calcium salts, together with small amounts of magnesium, iron and other mineral salts in tissues. Remember that calcification occurs due to the massive concentration gradient for calcium on the outside of the cell to the inside. This is because the concentration of Ca inside the cell is a meager 10^-7 M, while it is 10^-3 outside the cell. Thus the concentration of Ca is 1000 times higher on the outside of the cell than the inside!
This type of calcification can be classified in two different ways:
- The presence of absence of a mineral balance.
- This is simply based on where calcification is most pronounced.
- 4 Types Based on Location:
- Skeletal Calcification
- Extraskeletal Calcification eg. Breast Calcification, Cutaneous Calcification
- Brain e.g.. Fahr’s Syndrome
- Tumour Calcification eg. calcification of ovarian tumours
Presence of Absence of Mineral Balance
Basically, this classification refers to whether or not the cell is alive. If the cell is dead, then it should be obvious that because its Ca2+ pumps do not work now, it will be unable to maintain Calcium homeostasis. This means it can do nothing to stop the massive flow of Ca2+ from outside the cell to inside. Note that since it is not a change in concentration of Ca2+ inside or outside the cell that triggers the calcification, the mineral balance remains normal. Thus, this type of calcification that occurs in dying tissues despite normal serum levels of Ca2+ is known as dystrophic calcification.
In contrast, when there is a change in concentration of Ca2+ levels such that the concentration of Ca2+ increases outside the cell (hypercalcemia), the 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, is known as metastatic calcification.
Dystrophic calcification, as explained above, is the type of calcification that occurs in areas of necrosis, regardless of whether they are liquefactive, coagulative, caseous etc. Just remember that “dystrophic” literally means “degenerated/dead,” so dystrophic calcification is screaming out to you that it occurs in dead cells. It is also very common in areas of fat necrosis, and in foci of enzymatic necrosis of fat. Thus, we can see why it is very common in atheromas of atherosclerosis (explained lower down). However, the most common site of dystrophic calcification is in the caseous necrosis of tuberculosis. This is actually due to the sheer number of leukocytes and cells dying within the region of caseous necrosis due to tuberculosis. (Caseous necrosis and this process is explained in Necrosis). Hence, tuberculous lymph nodes are so calcified that they are essentially converted to stone (hence the flaky appearance of caseous necrosis macroscopically – cool!)
It occurs even when there is no systemic elevation of the Ca2+ concentration throughout the body and serum Ca2+ levels are normal and is believed to be significantly promoted by the activation of phosphatases that activate during necrosis or severe cell damage. Ca2+ first binds to the phospholipid in damaged cell membranes and membranes of organelles, promoting Ca2+ 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 (because that’s how chemistry works) to form a visible calcium microcrystals.
Macroscopically then, dystrophic calcification produces calcium crystals that appear as fine, white granules or clumps, often felt as gritty deposits. Microscopically, it appears as basophilic granules (or amorphous deposits sometimes) located inside and outside cells.
While dystrophic calcification is reversible, it is possible for it to become very dangerous and pathological. For example, in a scenario where a patient is of old age, and his heart valves are damaged, dystrophic calcification occurs within the heart valves, hardening them and impeding blood flow. This results in a life-threatening condition known as calcific aortic stenosis.
(Diagram courtesy Robbins and Cotran’s Pathologic Basis of Disease, 9th ed.)
Furthermore, if enough dystrophic calcification occurs in areas of soft tissue due to necrosis, then bone formation may eventually occur, resulting in heterotrophic ossification (formerly known as myositis ossificans). Heterotrophic ossification may be harmless, but if it occurs in inappropriate regions, can cause severe problems for the individual. For example, in the condition above, ossification of the elbow joint, the range of motion is severely depressed.
Another condition is cutaneous calcification, or calcinosis cutis. This occurs due to massive cell death in the skin such as during a large skin lesion or inflammatory process, after which dystrophic calcification occurs over a large area and calcifies soft tissue located under the skin, via the deposition of calcium phosphate, or hydroxyapatite crystals (otherwise usually located in bones).
When calcification occurs in atheroscleorsis, it is known as Monckeberg’s arteriosclerosis, or medial calcific sclerosis, where calcium deposits in the muscular middle third of the layers of the artery, or the tunica media.
Finally, it is important to mention 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. Thus, it is essentially a single necrotic cell with a round collection of calcium around it. The single necrotic cell is like a grain of sand among the other cells, and hence, psammoma is in fact, greek for sand. It occurs most commonly in papillary carcinomas (such as papillary thyroid carcinomas) and is a very useful marker for carcinomas of the papillary variety. Metastatic Calcification
Metastatic Calcification occurs in cell tissues whenever hypercalcemia is present throughout the body. It should be noted that while hypercalcemia causes metastatic calcification, it can accentuate dystrophic calcification, simply by increasing the concentration gradient for Ca2+ into the cell. Dystrophic calcification is thus NOT dependent on hypercalcemia simply because it can still occur in its absence.
Thus, in discussing metastatic calcification, we can discuss hypercalcemia. Broadly, there are 4 main causes of hypercalcemia that can cause metastatic calcification.
- 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 (eg. multiple myeloma, leukemia, osteosarcoma) or diffuse skeletal metastases (e.g. breast cancer), accelerated bone turnover (eg. Paget’s Disease), or immobilization.
- 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.
It may also occur in aluminum intoxication that occurs in chronic renal dialysis, and in milk-alkali syndrome, due to ingestion of a large amount of Calcium containing foodstuffs.
To categorize, metastatic calcification occurs in elevated levels of Calcium in serum due to deranged metabolism, increased absorption, or decreased excretion of Ca2+ and related minerals from the body.
Since hypercalcemia is a body-wide condition, we now come across a major difference between metastatic calcification and dystrophic calcification – metastatic calcification follows hypercalcemia and thus occurs in diffuse areas around the entire body in times of hypercalcemia. In contrast, dystrophic calcification occurs in localized areas of cell death.
This is actually why metastatic calcification is named such – because like metastatic cancer, it “travels” around the body. So you can use that to remember this. Despite this, metastatic calcification is most common in particular areas, namely the interstitial tissues of gastric mucosa, kidneys, lungs, systemic arteries and pulmonary veins. These areas all have in common, an acidic secreting component. Thus, usually, to balance the acid secreting component, they contain an alkaline compartment that predisposes them to metastatic calcification.
Macroscopically and microscopically, they appear similar to dystrophic calcifications, since in essence, they are both simply calcifications caused by different causes. Thus, they can appear as the noncrystaline amorphous deposits, or as crystalline calcium phosphate or hydroxyapatite crystals.
Pathologically, metastatic calcification does not produce many pathologies, but if allowed to build up, can lead to a host of problems body-wide. In the kidneys, large build up of Calcium in its tissues will lead to nephrocalcinosis, that causes massive renal damage. Similarly, pulmonary calcinosis causes massive lung damage. Clinically, the most important significance of metastatic calcification is that the patient is suffering from hypercalcemia, and thus mainly serves as a marker for diagnosis.
Other Types of Calcium Depositions in the Body
Additionally, one other noteworthy, but rare type of soft tissue calcium deposition is known as tumoral calcinosis (notice I did not call it calcification) – we will see why just now). 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. Note that it is not, in fact, a tumor, despite the name (sigh, thanks medicine). 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, NOT hypercalcemia. Thus, this condition has nothing to do with Ca2+ concentrations in the body, and this is important to keep in mind.
In all cases, any deposition of Ca2+ in soft tissues is known as calcinosis, be it dystrophic, metastatic, or tumoral.
Chondrocalcinosis is another type of soft tissue calcification that 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. In terms of mineral ions, hyperparathyroidism, hypothyroidism, iron overload (hemochromatosis), hypophosphatemia and hypomagnesia are found to have a correlation with chondrocalcinosis.
Splenic Siderotic Nodules, or Gamma-Gandy Bodies are located in the spleen, and are found in portal hypertension. This hypertension will lead to a small microheamorhage, which results in the accumulation of two substances: haemosiderin, an iron storage complex, and calcium, in the connective tissue stroma. Following this, a fibroblastic reaction which produces an external framework for the accumulation occurs, producing a gamma-gandy body, which is really a small, focal deposit of iron and calcium within fibrous and elastic tissue of the spleen, resulting in small nodules less than 1mm wide.
Yellow Arrowheads: Haemosiderin pigment.
Black Arrows: Gamma-Gandy Bodies
They are also associated with sickle cell anemia, hemolytic anemias, cardiac myxomas, neoplasms of the spleen, leukemias and lymphomas.
That’s all guys! Here are some extra resources for you all: