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With hypokalemia, hypo- means under and -kal- refers to potassium, and -emia refers to the
blood, so hypokalemia means lower than normal potassium levels in the blood, generally under
3.5 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.
And 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 the sweat.
So, in order for there to be too little potassium in the blood, or hypokalemia, there are two
possibilities, the first is an external balance shift most often caused by an increase in
potassium excretion in the kidneys, which lowers the level of potassium in the blood,
and the second is an internal balance shift where potassium moves into of cells, from
the interstitium and blood.
One potential cause of an internal potassium balance shift is having excess insulin.
This is because, after a meal, glucose increases in the blood, and at the same time insulin’s
released, which binds to cells and stimulates the 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, and so they use exogenous insulin,
meaning an injection or infusion of insulin.
In rare cases, insulin overdose can cause enough potassium uptake into cells as to cause
hypokalemia.
Another cause of an internal potassium balance shift could be an alkalosis, which is when
the blood becomes too alkaline, in other words, there’s a lower concentration of hydrogen
ions—meaning a higher blood pH.
One way the body can decrease blood pH is by moving hydrogen ions out of cells and into
the blood.
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 alkalosis, hydrogen ions leave cells and potassium ions
enter the cells and leave the blood, resulting in hypokalemia.
That being said, not all acid-base disturbances affect potassium levels.
For example, in respiratory alkalosis due to low carbon dioxide levels in the blood,
potassium levels aren’t typically affected because CO2 is lipid soluble and freely moves
into or out of cells without being exchanged for potassium, therefore no hypokalemia.
Certain catecholamines can also shift potassium movement into cells, and this is via the 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 agonists and alpha-adrenergic antagonists, both cause
a shift in potassium into cells and out of the blood.
Alright, on to external potassium balance shifts resulting in hypokalemia, which has
to do with potassium intake or excretion.
With regards to intake, simply not taking enough potassium in can lead to hypokalemia,
like in the case of anorexia, prolonged fasting, or specific types of diets.
Most other cases, though, have to do with the kidney’s ability to regulate what stays
in the blood and gets excreted into the urine.
The kidney does this by the processes of filtration, reabsorption, and secretion in the nephron.
First off, potassium is freely filtered from the blood into the urine at the glomerulus.
After that, about 67% is reabsorbed in the proximal convoluted tubule, and an additional
20% is reabsorbed in the thick ascending limb.
And that leaves 13% of the initial amount, right?
And at this point the distal tubule and collecting ducts of the nephron can either reabsorb or
secrete potassium depending on what the body needs.
Now, reabsorption in this area is taken care of by the alpha-intercalated cells, while
secretion is controlled by the principal cells.
Typically for people on a normal diet, more potassium is secreted then reabsorbed at this
stage, and it could even be that all of the remaining potassium is secreted out if it’s
simply not needed.
Now, an important hormone that helps regulate potassium reabsorption or secretion in the
kidneys is aldosterone.
Aldosterone increases the number of sodium channels on the lumen side of the principal
cell and and sodium-potassium pumps on the basolateral side of the principal cells.
This allows sodium to move from the tubule into the cell, and then get pumped into the
blood by the sodium-potassium pumps.
As the pumps collectively move more sodium into the blood under the influence of aldosterone,
more potassium gets pumped into the cell which raises the intracellular potassium concentration.
Having more intracellular potassium and also having more potassium channels promotes potassium
secretion.
Having said all that, in situations where somebody produces too much aldosterone, like
primary hyperaldosteronism, then there’s more potassium secretion by the principal
cells, meaning more gets excreted, and that means less potassium is retained, causing
hypokalemia.
Other pathological conditions that cause increased aldosterone levels include compensated heart
failure and cirrhosis.
Commonly used diuretics, like loop diuretics and thiazide diuretics, also increase potassium
excretion and can lead to hypokalemia.
These diuretics inhibit sodium reabsorption upstream of the principal cells, which means
more sodium is delivered downstream to the principal cells.
As a result, more sodium enters the principal cells and is available for the sodium-potassium
pump, which pumps sodium out into the blood and pumps potassium into the cell, creating
a relatively high potassium concentration in the principal cell.
In addition, these diuretics also allow more water to remain in the lumen, creating a relatively
low potassium concentration in the lumen.
Taken together, a relatively high potassium concentration in the principal cell and a
relatively low potassium concentration in the lumen, increases the potassium gradient
and causes a lot of potassium to get secreted and excreted in the urine, leading to hypokalemia.
Another external balance shift causing hypokalemia is increased losses of gastrointestinal secretions,
typically due to vomiting and diarrhea.
Now, the upper GI tract actually only secretes a small amount of potassium, so direct losses
via vomiting are usually minimal.
But the loss of stomach acid leads to metabolic alkalosis, which as we already saw, can lead
to hypokalemia.
Relative to the upper GI tract, the lower GI tract secretes more potassium, so more
gets directly lost in the feces in cases of chronic diarrhea, like from infections, inflammatory
bowel diseases, as well as laxative abuse.
Finally, a very small amount of potassium is also lost in sweat, which could be relevant
for individuals who exercise a lot in a hot climate.
Alright, so there are all these ways to develop hypokalemia, but what happens when somebody
has hypokalemia?
Well remember that the concentrations of potassium inside and outside of cells is really—super—important
for maintaining the resting cell membrane potential, and ultimately for allowing a cell
to depolarize and a muscle to contract, and that includes all muscles—skeletal, smooth,
and cardiac muscles.
So, with low potassium in the blood, the membrane potential can hyperpolarize, or become more
negative.
This means that these muscle cells become less reactive to stimuli.
Diminished contractions of smooth muscles can lead to constipation.
Diminished skeletal muscle contractions can lead to muscle weakness, cramps, and flaccid
paralysis, which tends to begins in the lower extremities and ascends upward.
Respiratory muscles may also be affected which leads to respiratory depression.
Finally, hypokalemia can affect cardiac muscle contractions, which can lead to cardiac arrhythmias
as well as cardiac arrest.
Hypokalemia is diagnosed based on the presence of an low levels of potassium in the blood,
generally below 3.5 mEq/L. It’s also important to get an electrocardiogram, which typically
shows a prolonged QT interval, appearance of a U wave, and atrial or ventricular tachyarrhythmias.
In patients with severe hypokalemia, the main goal of treatment is to normalize potassium
levels.
This is done by reducing ongoing potassium losses by treating underlying causes like
vomiting and diarrhea and using potassium-sparing diuretics if diuretic therapy is required,
as well as replenishing potassium stores with supplementation.
Alright, as a quick recap, hypokalemia describes a low concentration of potassium in the blood,
which can be the result of internal potassium balance shift where potassium moves into the
body’s cells, as well as an external potassium balance shift having to do with either low
intake or high excretion of potassium.
Either way the low potassium levels leads to issues with muscle contractions, which
could be smooth, skeletal, or cardiac muscles.