Content Reviewers:Rishi Desai, MD, MPH
With hypercalcemia, hyper -means over and -calc- refers to calcium, and -emia refers to the blood, so hypercalcemia means higher than normal calcium levels in the blood, generally over 10.5 mg/dL.
Now, calcium exists as an ion with a double positive charge - Ca2+ - and it’s the most abundant metal in the human body.
So I know what you’re thinking - yeah, we’re all pretty much cyborgs,- Cool, huh?
So about 99% of that calcium is in our bones in the form of calcium phosphate, also called hydroxyapatite.
The last 1% is split so that the majority, about 0.99% is extracellular - which means in the blood and in the interstitial space between cells, and 0.01% is intracellular or inside cells.
High levels of intracellular calcium causes cells to die.
In fact, that’s exactly what happens during apoptosis, also known as programmed cell death.
For that reason, cells end up spending a lot of energy just keeping their intracellular calcium levels low.
Now, calcium gets into the cell through two types of channels, or cell doors, within the cell membrane.
The first type are ligand-gated channels, which are what most cells use to let calcium in, and are primarily controlled by hormones or neurotransmitters.
The second type are voltage-gated channels, which are mostly found in muscle and nerve cells and are primarily controlled by changes in the electrical membrane potential.
So calcium flows in through these channels, and to prevent calcium levels from rising too high, cells kick excess calcium right back out with ATP-dependent calcium pumps as well as Na+-Ca2+ exchangers.
In addition, most of the intracellular calcium is stored within organelles like the mitochondria and smooth endoplasmic reticulum and is released selectively just when it's needed.
Now, the majority of the extracellular calcium is split almost equally between two groups - calcium that is diffusible and calcium that is not diffusible.
Diffusible calcium is separated into two subcategories: free-ionized calcium, which is involved in all sorts of cellular processes like neuronal action potentials, contraction of skeletal, smooth, and cardiac muscle, hormone secretion, and blood coagulation, all of which are tightly regulated by enzymes and hormones.
The other category is complexed calcium, which is where the positively charged calcium is ionically linked to tiny negatively charged molecules like oxalate, which is a small anions that’s normally found in our blood in small amounts.
The complexed calcium forms a molecule that’s electrically neutral and small enough to cross cell membranes, but, unlike free-ionized calcium is not useful for cellular processes.
Finally, though, there’s the non-diffusible calcium which is bound to negatively charged proteins like albumin and globulin, and the resulting protein-calcium complex is too large and charged to cross membranes, leaving this calcium also uninvolved in cellular processes.
When the body’s levels of extracellular calcium change, it’s detected by a surface receptor in parathyroid cells called the calcium-sensing receptor.
This affects the amount of parathyroid hormone that gets released by the parathyroid gland.
The parathyroid hormone gets the bones to release calcium, and gets the kidneys to reabsorb more calcium so it's not lost in the urine and synthesize calcitriol also known as active vitamin D.
Active vitamin D then goes on to increase calcium absorption in the gastrointestinal tract.
All together, these effects help to keep the extracellular levels of calcium within a very narrow range, between 8.5 to 10 mg/dl.
Sometimes, though, total calcium levels in the blood, which includes both diffusible and non-diffusible - blood can vary a bit, depending on the blood's pH and protein levels.
This happens because albumin has acidic amino acids, like glutamate and aspartate, which have some carboxyl groups that are in the form of COO- or COOH.
Overall the balance of COOi and COOH changes based on the pH of the blood.
Now, when there’s a low pH, or acidosis, there are plenty of protons or H+ ions floating around, and a lot of those COO- groups pick up a proton and become COOH.
More COOH groups make albumin more positively charged, and since calcium is positively charged, these two repel each other, and this decreases bound calcium and increases the proportion of free ionized calcium in blood.
So as more protons bind albumin, more free ionized calcium builds up in the blood, and so even though total levels calcium are the same, there’s less bound calcium and more ionized calcium, which remember is important for cellular processes and can lead to symptoms of hypercalcemia.