Hypocalcemia

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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.