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. 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
are 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, the bone-building cells, and some tumors 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 being absorbed
in the gut. Finally, there are some medications like thiazide
diuretics which increases 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, 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 high level
of calcium in the blood, generally above 10.5 mg/dL. An electrocardiogram might have changes 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 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 causes excitable cells
to be less…excitable, which result in slow reflexes, muscle weakness, and constipation.

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