With hyper-calcemia, 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 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 cause cells to die. In fact, that’s exactly what happens during apoptosis, also known as programmed cell death.
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 anion 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.
Altogether, 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 the blood. So as more protons bind albumin, more free
ionized calcium builds up in the blood, and so even though total levels of calcium
are the same, there’s less bound calcium and more ionized calcium, which
remembers is important for cellular processes and can lead to symptoms of
hypercalcemia. Also, any condition that results in hyperalbuminemia or high
albumin levels causes there to be a higher concentration of protein-bound
calcium, while free ionized calcium concentrations stay essentially the same
due to hormonal regulation.
This is therefore called false
hypercalcemia or pseudohypercalcemia, since the concentration of bound calcium
increases but the concentration of free ionized calcium stays the same. Even
though this is rare, it can happen in people with dehydration - where albumin
gets very concentrated. Now, True hypercalcemia might be caused by increased
osteoclastic bone resorption, which is actually the most common cause, and this
is where osteoclasts, which are little bone-eating cells, frantically break
down the bone and release calcium into the blood. This might happen when the
parathyroid gland becomes overgrown and releases more parathyroid hormone.
Another well-known cause of
hypercalcemia is malignant tumors, some of which secrete parathyroid
hormone-related protein or PTHrP, a hormone that mimics the effect of
parathyroid hormone which stimulates the osteoclasts. Alongside these
osteoclast cells, there’re also osteoblast cells, bone-building cells, and
some tumors that cause osteoblasts to die off. Overstimulated osteoclasts without
enough osteoblasts can result in lytic bone lesions which are commonly seen in
some malignancies. Another cause of hypercalcemia is excess vitamin D either
through the diet or through supplements, which can cause too much calcium to be absorbed in the gut. Finally, there are some medications like thiazide
diuretics which increase calcium reabsorption in the distal tubule of the
kidney which contributes to hypercalcemia. High levels of ionized calcium
affect a variety of cellular processes, in particular, electrically active
neurons.
Normally, calcium ions stabilize the
resting state of the sodium channels, which prevents them from spontaneously
opening and letting sodium ions enter the cell. With high levels of
extracellular calcium, voltage-gated sodium channels are less likely to open
up, which makes it harder to reach depolarization, and makes the neuron less excitable.
This is what causes slower or absent reflexes, which is a classic symptom of
hypercalcemia. The sluggish firing of neurons also leads to slower muscle
contraction, which causes constipation and generalized muscle weakness. In the
central nervous system, the hypercalcemia causes confusion, hallucinations, and
stupor. In most cases, when there’s too much calcium in the blood, the kidneys
try to dump it into the urine - causing hypercalciuria or excess calcium in the
urine. Hypercalciuria leads to a loss of excess fluid in the kidneys causing an
individual to get dehydrated, and the combination of hypercalciuria and
dehydration can lead to calcium oxalate kidney stones.
Hypercalcemia is diagnosed based on a high level of calcium in the blood, generally above 10.5mg/dl. An
electrocardiogram might have changed like bradycardia, AV block, shortening of
the QT interval, and sometimes in the precordial leads the appearance of an
Osborn wave. To identify the cause, lab tests are typically done, looking at
parathyroid hormone, vitamin D, albumin, phosphorus, and magnesium levels. In
hypercalcemia, the main goal is to lower calcium levels using medications that
reduce calcium in the blood. One approach is to increase urinary excretion of
calcium, which can be done by rehydrating an individual which causes more
calcium to get filtered out.
In addition, loop diuretics can be
helpful because they inhibit calcium reabsorption in the loop of Henle, leaving
calcium in the lumen of the nephron to get excreted. Another approach is to
increase gastrointestinal excretion, by using glucocorticoids to decrease intestinal
calcium absorption, which allows it to instead simply pass through the gut without
getting absorbed. Finally, you can prevent bone resorption by using
bisphosphonates or calcitonin to inhibit osteoclasts.
Alright, as a quick recap,
hypercalcemia describes a high concentration of free ionized calcium in the
blood, which most commonly results from excess parathyroid hormone as well as malignancies.
High calcium levels cause excitable cells to be less...excitable, which results
in slow reflexes, muscle weakness, and constipation.
Thank you