Hyperkalemia

With hyperkalemia, hyper- means over and -kal- refers to potassium, and -emia refers to the blood, so hyperkalemia means higher than normal potassium levels in the blood, generally over 5.5 mEq/L.

Now, total body potassium can essentially be split into two components—intracellular and extracellular potassium, or potassium inside and outside cells, respectively.

The extracellular component includes both the intravascular space, which is the space within the blood and lymphatic vessels and the interstitial space, the space between cells where you typically find fibrous proteins and long chains of carbohydrates which are called glycosaminoglycans.

Now, the vast majority, around 98%, of all of the body’s potassium is intracellular, or inside of the cells.

In fact, the concentration of potassium inside the cells is about 150 mEq/L whereas outside the cells it’s only about 4.5 mEq/L.

Keep in mind that these potassium ions carry a charge, so the difference in concentration also leads to a difference in charge, which establishes an overall electrochemical gradient across the cell membrane. This is called the internal potassium balance.

This balance is maintained by the sodium-potassium pump, which pumps 2 potassium ions in for every 3 sodium ions out, as well as potassium leak channels and inward rectifier channels that are scattered throughout the membrane.

This concentration gradient is extremely important for setting the resting membrane potential of excitable cell membranes, which is needed for normal contraction of smooth, cardiac, and skeletal muscle.

Also, though, in addition to this internal potassium balance, there’s also an external potassium balance, which refers to the potassium you get externally through the diet every day.

On a daily basis the amount of potassium that typically gets taken in usually ranges between 50 mEq/L to 150 mEq/L, which is way higher than the extracellular potassium concentration of 4.5 mEq/L, so your body has to figure out a way to excrete most of what it takes in.

This external balancing act is largely taken care of by the kidneys, where excess potassium is secreted into a renal tubule and excreted in the urine.

Also though, a small amount dietary potassium is also lost via the gastrointestinal tract and sweat.

So, in order for there to be too much potassium in the blood, or hyperkalemia, there are two possibilities.

The first is an external balance shift, which is most often caused by a decrease in sodium excretion in the kidneys, which raises the level of potassium in the blood.

The second is an internal balance shift where potassium moves out of cells, and into the interstitium and blood. One potential cause of an internal potassium balance shift is insulin deficiency.

This is because, after a meal, glucose increases in the blood, and at the same time, insulin gets released which binds to cells and stimulates uptake of that glucose.

Insulin also increases the activity of the sodium/potassium pump, which pulls potassium into cells.

People with type I diabetes don’t make enough insulin, so when they eat a meal—especially a meal with a lot of potassium—that potassium sits in the blood instead of being taken into cells, and this causes hyperkalemia.

Another cause of an internal potassium balance shift could be an acidosis, which is when the blood becomes too acidic, in other words, there’s a higher concentration of hydrogen ions—which means a lower blood pH.

One way the body can increase the blood pH is by moving hydrogen ions out of the blood and into cells.

To accomplish this, cells use a complex series of multiple ion channels, exchangers, and pumps to exchange hydrogen ions for potassium ions across the cell membrane.

So in order to help compensate for an acidosis, hydrogen ions enter cells and potassium ions leave the cells and enter the blood, which might help with the acidosis, but results in hyperkalemia.

Now, this isn’t always the case for acidosis, though. in respiratory acidosis, potassium levels aren’t affected because CO2 is lipid soluble and freely moves into cells without being exchanged for potassium, therefore no hyperkalemia.

Similarly, when there’s a metabolic acidosis from excess organic acids like lactic acid and ketoacids, protons can enter cells with the organic anion rather than having to get exchanged for potassium ions.

Certain catecholamines can also shift potassium out of cells, and this is via beta-2-adrenergic and alpha-adrenergic receptors on cell membranes. When activated, beta-2-adrenergic receptors stimulate the sodium-potassium pump, which pulls potassium from the blood into cells.

Meanwhile alpha-adrenergic receptors cause a shift of potassium out of cells via calcium-dependent potassium channels.

So, that said, beta-2-adrenergic antagonists, also known as beta blockers, and alpha-adrenergic agonists, both cause a shift in potassium out of the cells and into the blood.

Another important mechanism is hyperosmolarity, which is where there is an increased extracellular osmolarity, relative to the intracellular space. This osmotic gradient pulls water out of cells and into the extracellular space.

Less water in the cells increases the intracellular potassium concentration, which increases potassium’s concentration gradient, and pushes more of it out of the cell and into the interstitium and blood. Cell lysis is yet another cause of hyperkalemia.

Since so much potassium is kept within the cell, when a large number of cells die or lyse, potassium is released into the blood, which causes hyperkalemia.

Examples of large-scale cell lysis are severe burns, rhabdomyolysis or breakdown of skeletal muscle, and tumor lysis as a result of chemotherapy. A final example of internal potassium balance leading to hyperkalemia is exercise. During exercise while the body and the body’s cells are working harder, more cellular ATP, which is the molecular unit of currency, gets consumed.

The depletion of ATP triggers potassium channels on the membrane of muscle cells to open up, which allows potassium to moves down its electrochemical gradient and out of the cell.