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Physical Medicine and Rehabilitation

Hypocalcemia – causes, symptoms, diagnosis, treatment, pathology

Hypocalcemia – causes, symptoms, diagnosis, treatment, pathology

With hypocalcemia, -hypo means below, calc-
refers to calcium, and -emia refers to the blood, so hypocalcemia means lower than normal
calcium levels in the blood, generally less than 8.5 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. Anyways, 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, whereas 0.01% is intracellular. 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 using a ton
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 getting too high, cells kick excess calcium right
back out with ATP-dependent calcium pumps as well as sodium calcium 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,
the calcium in the blood and interstitium, 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 anion that are normally found in our blood in small
amounts. The complexed calcium forms a molecule that’s
electrically neutral but unlike free-ionized calcium is not useful for cellular processes. Both of these are called diffusible because
they’re small enough to diffuse across cell membranes. Finally though there’s the non-diffusible
calcium which is bound to negatively charged proteins like albumin, 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
as well as synthesize calcitriol also known as 1,25-dihydroxycholecalciferol also known
as active vitamin D. Active vitamin D then goes on to cause the gastrointestinal tract
to increase calcium absorption. All together, these effects help to keep the
extracellular levels of calcium within a narrow range, between 8.5 to 10 mg/dl. Sometimes though, total calcium levels in
the blood, which includes both diffusible and non-diffusible – in 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 COO- and COOH changes
based on the pH of the blood. When there’s a high pH, or alkalosis, there
are very few protons floating around, and so those carboxyl groups tend to be in the
COO- form. More COO- groups tend to make albumin negatively
charged, and since calcium is positively charged, opposites attract, and the negatively charged
albumin latches onto calcium, which means there’s more bound calcium and less free-ionized
calcium in the blood. And so even though the total levels of calcium
are the same, there’s less ionized calcium which is the one that’s important for cellular
processes and can lead to symptoms of hypocalcemia. Also, any condition that results in hypoalbuminemia
or low albumin levels, would lead to a loss of bound calcium, while at the same time free
ionized calcium concentrations stay essentially the same due to hormonal regulation. This is therefore called false hypocalcemia
or pseudohypocalcemia, since there’s less overall calcium due to less bound calcium,
but the free ionized calcium levels are still the same. Alright so in order for there to be too little
calcium in the blood, or true hypocalcemia, there are two possibilities, less calcium
entering the blood, or too much calcium leaving the blood. Less calcium entering the blood is the most
common cause and can be due to hypoparathyroidism, or lower levels or lower activity of parathyroid
hormone. This can be caused surgical removal or autoimmune
destruction of the parathyroid gland, as well as congenital problems involving the parathyroid
gland like DiGeorge syndrome, or deficiency in magnesium which is needed for parathyroid
hormone production. Also, low levels of vitamin D can also lead
to hypocalcemia, and can be caused by a deficient diet, malabsorption, cirrhosis, a lack of
sunlight, and chronic renal failure, just to name a few. And then there’s the second cause – too
much calcium leaving the blood. This might happen when too much ionized calcium
is excreted. Normally, calcium filters from the blood into
the glomerulus of the kidney but is then reabsorbed back into the blood by the nephron so that
it isn’t lost. In kidney failure, the nephron doesn’t effectively
reabsorb calcium, which allows it to get excreted into the urine. A different example would be tissue injury,
like burns, rhabdomyolysis, and tumor lysis syndrome where large numbers of cells die
releasing intracellular phosphate into the blood. The phosphate binds to the ionized calcium
and forms calcium phosphate, making it insoluble and effectively decreasing the total amount
in blood. Other inflammatory processes can also be a
cause, like acute pancreatitis because free fatty acids end up binding to ionized calcium,
which is also insoluble and precipitates out as a soap-like substance. Finally, ionized calcium levels can fall as
a result of having too many blood transfusions, because additives in the blood like citrate
and ethylenediaminetetraacetic acid or EDTA – can chelate or bind to calcium, forming
complexed calcium, which is an inactive molecule. Low levels of ionized calcium affect a variety
of cellular processes, in particular, electrically active neurons. Normally, the resting state of sodium channels
is stabilized by calcium ions, which prevents them from spontaneously opening and potentially
causing depolarization. With low levels of extracellular calcium,
voltage-gated sodium channels are less stable and more likely to open up, which allows the
cell to depolarize more easily, and makes the neuron more excitable. This can trigger tetany or the involuntary
contraction of muscles, a classic symptom of hypocalcemia. The spontaneous firing of neurons also leads
Chvostek’s sign, which is when facial muscles twitch after the facial nerve is lightly finger
tapped 1 cm below the zygomatic process. It also can cause Trousseau’s sign, which
is where a blood pressure cuff occludes the brachial artery, and that pressure on the
nerve is enough to make it fire, which results in a muscle spasm that makes the wrist and
metacarpophalangeal joints flex. Other symptoms include muscle cramps, abdominal
pain, perioral tingling which is tingling around the mouth, and in extreme cases – seizures. Hypocalcemia is diagnosed based on a low level
of calcium in the blood, generally below 8.5 mg/dL. Also an electrocardiogram might have changes
such as a prolonged QT, prolonged ST segment, and arrhythmias, like torsade de pointes and
atrial fibrillation. To identify the cause, lab tests are typically
done, which includes tests for parathyroid hormone, vitamin D, albumin, phosphorus, and
magnesium. In hypocalcemia, the main goal is to normalize
calcium levels using formulation like calcium gluconate, and if appropriate, vitamin D supplementation. Alright, as a quick recap, hypocalcemia describes
a low concentration of free ionized calcium in the blood, which most commonly results
from defective production of calcium controlling hormones, like parathyroid hormone and active
vitamin D. Low calcium levels, which can cause certain excitable cells to be…more excitable,
which result in tetany, muscle spasms, and cardiac dysfunction.

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