Trait: Blood Calcium Level
Dr Haran Sivapalan
April 23, 2019
What is calcium?
Calcium is a mineral that is essential for various roles in the body, including heart function, muscle contraction, nerve signalling and maintaining healthy bones.
Like other minerals (and vitamins), calcium is a micronutrient. This means, unlike fats, carbohydrate and protein (which are collectively termed ‘macronutrients’), we require calcium only in small quantities. Nevertheless, calcium is also considered to be a macromineral – it is needed in larger amounts compared to so-called ‘trace minerals’ such as copper and manganese.
Why is calcium important?
We often think of calcium as being particularly important for healthy bones and teeth. While this is undoubtedly true, calcium plays much broader (and often less widely known) roles in the body.
Several of the internal biochemical processes that keep cells alive are dependent on calcium. For example, calcium is often used as a second messenger to relay signals from receptors on the outside of cells to cause molecular changes deep within cells. Similarly, calcium is extremely important in cell signalling: the cascades of chemical reactions that allow cells to communicate with one another. Calcium is also an important cofactor, meaning it is required for several enzymes to function efficiently.
Many of calcium’s functions in the body stem from the fact that it forms an ion: an electrically charged atom. The movement of calcium (Ca2+) ions into and out of cells causes differences in electrical charge and voltage across cell membranes. This principle is central to heart contraction, skeletal and smooth muscle contraction, and nerve signalling.
On a related note, calcium ions regulate the activity of voltage-gated ion channels. These are special transporter proteins located on cell membranes that open and close to allow the passage of ions (charged atoms such as sodium Na+, potassium K+ and chloride Cl-) into and out of cells. As their name suggests, the opening and closing of these channels is triggered by changes in voltage across cell membranes. As calcium ions affect the voltage across cell membranes, changes in calcium levels can influence the opening and closing of voltage-gated ion channels and therefore the movement of other ions into and out of cells. This affects the function of so-called 'electrically-excitable' tissues - heart, nerve, muscle.
- Calcium is involved in several chemical reactions and signalling processes within cells.
- Calcium is required for healthy bones and teeth.
- Calcium ions are charged particles and play an important role in tissues which use electro-chemical signals (e.g. heart, nerves, muscle).
- Calcium ions are crucial for nerve, muscle and heart function.
Where is calcium stored in the body?
Our body has three main regions where it stores calcium:
The majority of calcium is stored in bone. Of this, most is in bone mineral – as part of a crystalline compound called hydroxyapatite. A much smaller proportion of bone calcium is in a reservoir that can be rapidly released into the blood and extracellular fluid (ECF).
Blood and extracellular fluid (ECF)
Extracellular fluid (ECF) is essentially a term for all body fluid that is outside of cells. This predominantly includes plasma (or serum*), the fluid component of blood, and interstitial fluid, the fluid that surrounds and baths cells.
Plasma and interstitial fluid are important as they contain ions (including calcium ions) and nutrients that cells require for various key processes.
In your blood plasma, about half of calcium is bound to proteins, particularly a protein called albumin. The remaining half is contained as free calcium ions – (this is sometimes referred to as ionized calcium).
As we will soon find out, your body strives to maintain constant levels of calcium ions in the blood plasma and interstitial fluid.
(Note that the consistency and concentration of ions in interstitial fluid bathing cells and blood plasma are closely related. For this reason, when we refer to changes in calcium levels in the blood, this also includes similar changes in calcium levels in interstitial fluid.)
* The term serum technically refers to the blood plasma (i.e. the fluid, non-cellular component of blood) without clotting factors. To keep things simple, we will use the terms blood serum and blood plasma interchangeably.
As mentioned earlier, calcium is extremely important for many of the internal signalling processes and chemical reactions that occur within cells. Cells store calcium in various internal organelles, including the mitochondria (which are responsible for cell respiration) and the endoplasmic reticulum (involved in the packaging and transport of proteins).
The amount of calcium within cells fluctuates considerably, depending on the activity of chemical reactions and signalling processes taking place. Intracellular calcium stores are replenished from calcium in blood plasma and interstitial fluid.
- Calcium is in three main 'reservoirs' in the body: in bones, in extracellular fluid (including blood serum/plasma), and inside cells.
- We are constantly shifting calcium between these three reservoirs.
- Our bodies maintain levels of calcium in the blood plasma within a tightly-controlled range. This is an example of 'homeostasis' - the maintenance of a constant internal environment.
Why do we need to regulate calcium levels in the blood?
Calcium supply for cells
In order for cells to use calcium for internal biochemical and signalling processes, they must have a consistent supply of calcium ions. This is provided by calcium in the blood plasma and interstitial fluid. Although cells have their own internal stores of calcium, these must be kept topped up from calcium ions supplied in the blood plasma.
Nerve and muscle function
Another major reason we maintain constant levels of calcium is related to the electrical properties of calcium ions. As described earlier, calcium ions carry electrical charge. Consequently, differences in the concentration of calcium ions inside and outside of cells can lead to changes in the voltage across cell membranes. By maintaining a constant level of calcium in blood plasma and interstitial fluid, the voltage across cell membranes can be stabilized – which is particularly important for the effective function of nerve, muscle and heart cells.
More specifically, by stabilizing the voltage across cell membranes, calcium ions regulate the opening and closing of voltage-gated ion channels. When calcium levels in the blood drop, voltage-gated ion channels are more likely to open. This then causes an influx of other ions (e.g. sodium), which can cause nerve and muscle cells to become over-excitable and fire inappropriately. For example, muscle spasms can result from low levels of a calcium (a phenomenon called hypocalcaemic tetany).
Conversely, if calcium levels in the blood become excessively high, voltage-gated ion channels are more likely to remain closed. This hinders the ability of other ions to enter nerve and muscle cells, which makes it harder for nerve signals to be conducted.
If you’ve ever cut yourself shaving, you’ll notice that the bleeding soon stops. This is due to the formation of blood clots, which are made from a molecule called fibrin. Calcium is essential for the formation of fibrin and various other stages in blood clotting. Low levels of calcium in the blood can therefore delay blood clotting.
- Calcium levels in the blood serum are kept within a strict range.
- Maintaining constant levels of calcium ions ensures nerve, muscle and heart cells are not overly or insufficiently electrically excitable.
- Low serum levels of calcium can lead to muscle spasms.
- High serum levels of calcium can impair nerve signalling and muscle contraction.
- Calcium in the bloodstream can be used by cells for internal chemical reactions and signalling pathways.
- Calcium is needed to form blood clots and prevent excessive bleeding.
Which organs regulate calcium levels in the blood?
Calcium levels in the blood are kept within a strict range by constantly adjusting the rate at which calcium is absorbed from food, excreted in the urine, and converted into bone mineral.
In this sense, there are three main organs that regulate calcium levels:
When you eat food, calcium (and other nutrients) is absorbed into the bloodstream in the small intestine. Cells on the inner lining of the small intestine (called epithelial cells) have various calcium-binding and transporter proteins (e.g. calbindin and TRPV6) which facilitate the absorption of calcium. Vitamin D stimulates this process and enhances the absorption of calcium in the small intestine.
By increasing the rate of calcium absorption in the small intestine, levels of calcium in the blood serum can be raised.
You probably know that the role of the kidneys is to the ‘filter the blood’ and produce urine. On this note, calcium is filtered by the kidneys into the urine. Under normal conditions, however, most of this calcium is then reabsorbed by the kidney back into the bloodstream.
By altering the amount of calcium that is reabsorbed by the kidneys, we can adjust calcium levels in the blood serum. For example, when blood calcium levels become excessively high, we reduce calcium reabsorption in the kidneys (and excrete more calcium in the urine).
Conversely, stimulating reabsorption of calcium in the kidneys will increase blood calcium levels.
The majority of calcium is stored as bone mineral. By remodelling bone, that is breaking down or depositing new bone tissue, calcium can be released into or removed from the bloodstream.
To increase serum calcium levels, bone tissue can be broken down in a process called bone resorption. Bone resorption is carried out by specialised bone cells called osteoclasts. They secrete acid which dissolves bone and releases calcium (along with phosphate) into the blood plasma and interstitial fluid.
Conversely, we can inhibit osteoclast activity and bone resorption to decrease serum calcium levels.
- Calcium levels in the blood serum are affected by three main processes:
- Absorption of calcium ions in the small intestine.
- Reabsorption and excretion of calcium from/into the urine by the kidneys.
- Release of calcium ions into the bloodstream by breaking down bone.
How are serum calcium levels regulated?
As explained above, we can adjust serum calcium levels by altering three key processes:
- Calcium absorption in the small intestine.
- Calcium reabsorption/excretion in the kidneys.
- Calcium release from bone tissue.
The balance of these processes is coordinated by a system of hormones, including:
- Parathyroid hormone (PTH)– which is secreted by your parathyroid glands: a set of 4 small glands located in the neck. PTH works to increase serum levels of calcium.
- Vitamin D – the active form (1,25 dihydroxyvitamin D or ‘calcitriol’) of which is made by the kidneys. 1,25 Vitamin D (calcitriol) increases serum levels of calcium.
- Calcitonin – which is secreted by the thyroid gland in the neck. Calcitonin works to decrease serum levels of calcium. In humans, it is thought that the action of calcitonin on calcium levels is less significant than that of parathyroid hormone.
- Serum calcium levels are controlled by three main hormones: Parathyroid hormone (PTH), Active Vitamin D (1,25 Vitamin D) an Calcitonin.
- PTH and Active Vitamin D increase serum levels of calcium.
- Calcitonin decreases serum levels of calcium.
What happens when serum calcium levels fall too low?
As with other homeostatic feedback mechanisms that maintain a constant internal environment for our tissues, the first stage in calcium regulation involves monitoring and sensing changes in serum calcium levels.
Your parathyroid glands, thyroid gland and kidneys have a special protein called the calcium-sensing receptor (CaSR). As its name suggests, the calcium sensing receptor detects changes in the amount of calcium circulating in the bloodstream.
When serum levels of calcium fall, less calcium binds to the CaSR. This triggers the parathyroid glands to produce more parathyroid hormone (PTH).
PTH has several effects in the body, all of which lead to increased calcium in the blood:
PTH stimulates bone resorption
PTH causes bones to immediately release calcium ions into the blood plasma and interstitial fluid. This process is facilitated by special bone cells called osteoblasts.
In the longer term, it also stimulates the production of more osteoclasts. Osteoclasts are cells responsible for bone resorption: they break down bone tissue and release calcium into the bloodstream.
PTH stimulates reabsorption of calcium in the kidneys
PTH causes tubules in the kidneys to reabsorb more calcium into the bloodstream and excrete less calcium in the urine.
Note also that less calcium binding to CaSR in the kidneys also directly stimulates the kidneys to reabsorb more calcium.
PTH stimulates the kidneys to produce active Vitamin D
Vitamin D, the ‘sunshine vitamin’, is obtained from our diet and also made by our skin using sunlight. This form of Vitamin D, however, is inactive. Vitamin D is subsequently converted into its active form: 1,25 dihydroxyvitamin D (or calcitriol) by the kidneys.
PTH stimulates the kidneys to produce more active Vitamin D (calcitriol). Active Vitamin D then also further elevates serum calcium levels by stimulating bone resorption, increasing calcium reabsorption in the kidneys and, most significantly, increasing absorption of calcium by the small intestine.
- The calcium-sensing receptor (CaSR) detects changes in serum calcium levels.
- When serum calcium is low, CaSR stimulates the parathyroid glands to produce parathyroid hormone (PTH).
- PTH restores/increases serum calcium levels.
- PTH increases calcium reabsorption, promotes bone resorption and stimulates the formation of active vitamin D.
- Vitamin D enhances absorption of calcium from the diet in the small intestine.
What happens when serum calcium levels become too high?
When calcium levels in the blood serum rise, more binds to the CaSR protein in the parathyroid glands. This suppresses the release of the PTH.
Similarly, activation of the CaSR protein in kidneys inhibits the reabsorption of calcium. This leads to a greater loss of calcium in the urine.
Your thyroid gland, a larger gland in the middle of your neck, also plays a role in regulating serum calcium levels. Again this is mediated by the CaSR protein. When levels of calcium become too high, cells in your thyroid gland called C-cells secrete a hormone called calcitonin.
Calcitonin reduces levels of calcium.
It does this in two main ways:
- Calcitonin inhibits bone resorption, so less calcium is released from bone into the bloodstream.
- Calcitonin inhibits reabsorption of calcium by the kidneys, so more is excreted in the urine.
How do genes influence your serum calcium levels?
There are several genes that affect calcium metabolism and therefore influence your blood serum levels of calcium. Perhaps the most well researched is the CASR gene, which encodes the CaSR Calcium-Sensing Receptor protein.
Variants of this gene affect how well your parathyroid glands and kidneys respond to changes in serum calcium levels. They therefore partly influence your risk of low or high blood calcium levels.