Hypokalaemia

Potassium is found in bananas. It's also found in your body, at about 40-50mmol/kg of body weight, meaning the typical Australian (72kg F, 87kg M) holds 2880-4350mmol (112.6-170.1g) of potassium.

Thanks to sodium, potassium, and the Na+/K+ ATPase pump (3Na+ out, 2K+ in, 1 ATP used), cells have a negative membrane potential. This is further evidenced by the difference in intracellular vs extracellular potassium content, at ~140-150mmol/L intracellularly, and 3.5-5mmol/L in serum (though, this range may differ between pathologists, i.e. SA Path reports 3.5-5.2mmol/L on UEC, some other labs 3.5-5.5mmol/L).

Hypokalaemia (HypoK)

Because our bodies effectively compensate for hypokalaemia via intracellular>extracellular potassium shift (and reducing renal potassium excretion), by the time changes are seen in the blood test, the intracellular (sequestered) component will have reached the end of it's compensatory ability. Especially in chronic hypokalaemia, by the time serum tests show hypokalaemia, the cells themselves are likely to be K+ deplete.

Please note that in acute scenarios (i.e. panic attacks with respiratory alkalosis), or cases where intracellular uptake is responsible (see below), intracellular stores may not be deplete.

Cells cannot absorb enough potassium from a serum which is itself deplete. The cell's lack of cations (potassium!!) leads to a widened charge difference between intracellular and extracellular spaces (the extracellular space still has lots of sodium), making the action potential harder to trigger. Ultimately, hypokalaemia hyperpolarises our cells. 

Inadequate Intake

Includes anorexia, dementia, inadequate TPN formulation, or starvation. Please comment if you would like an explanation of these causes.

Please consider that refeeding syndrome involves inadequate intake (and excessive excretion, kind of), but the crisis is more a problem of rapid intracellular shift as calories are reintroduced.

Excessive Excretion

GI losses (vomiting, diarrhoea, laxatives, enemas), renal losses from mineralocorticoid excess (Cushing's, Conn's, exogenous corticosteroids), type I and II renal tubular acidosis (RTA), intrinsic renal transport defects, hypomagnesaemia, diuretics (those that act prior to the collecting ducts), and dialysis.

Vomiting

Vomiting sees the loss of gastric juices.

How do we have gastric juice? Well, when you see food, the vagus nerve stimulates intrinsic nerves and G cells in the stomach. Stimulation of the intrinsic nerves causes an increase in chief and parietal cell activity, increasing gastric secretions. Stimulation of G-cells leads to gastrin secretion, which itself leads to increased enterochromaffin-like cell activity, leading to histamine secretion, and more chief (pepsinogen) and parietal (HCl) cell activation. You should also be aware that stretch from stomach content acts on stretch receptors which acts on intrinsic nerves, releasing acetylcholine to chief and parietal cells and directly stimulating the release of pepsinogen and HCl accordingly. 

It is K+/H+ ATPase that allows the ready secretion of protons into the stomach. Chlorine will follow via luminal Cl- ion channel (exporter), creating hydrochloric acid in the lumen. You might be thinking, wouldn't this lead to excessive potassium inside the cell?

Good thinking - but a luminal K+ ion channel (exporter) exists to dump excess intracellular potassium into the gastric juice.

Key learning 1: gastric juice is full of hydrogen chloride, potassium, and water. Therefore, vomiting typically causes a hypovolaemic, hypochloraemic, metabolically alkalotic, HYPOKALAEMIC patient.

Key learning 2: several mechanisms drive parietal cells: gastrin, histamine, and acetylcholine. PGE2 and PGI2 inhibit parietal cells. At the end of the day though, all these pathways converge to the K+/H+ ATPase pump. This is why PPIs are GOATed.

Sexy bonus learning 1: alkalosis itself can drive hypokalaemia (cells outside of the gastric tract buffer alkalosis, i.e. will absorb potassium and excrete protons (mainly via transmembrane ion gradients and transporters)). This effect may add to the hypokalaemia seen in vomiting.

Sexy bonus learning 2: secondary hyperaldosteronism can arise from hypovolaemia, which of course sees potassium wasted renally.

Sexy bonus learning 3: if a patient is vomiting terribly, their hypovolaemia may drive lactic acidosis as the blood volume drops so severely that organs are hypoperfused, and a switch to anaerobic metabolism occurs. To compensate, respiratory rate may increase, and produce a confusing picture where a patient is both metabolically alkalotic (vomiting) and HAG-metabolically-acidotic (lactic acidosis), yet compensating via an increased respiratory rate.

Diarrhoea

I think that diarrhoea has a less commonly known mechanism of causing hypokalaemia.

Example diarrhoea mech: when an organism like Enterotoxigenic E. Coli (ETEC) proliferates in the gut, it releases heat stable and heat labile toxin. Both toxins stimulate the luminal CFTR channels of intestinal cells, which leads to Cl- excretion. Sodium and water follow, and therefore luminal content increases.

Most know that the gastric tract secretes bicarbonate readily, in a layer of mucous which protects the tract from digestion from our microbiota. Less people know that the colon secretes potassium, upregulated when luminal content increases. 

Key learning 1: pathogens cause increased luminal content, which contains Cl-, Na+, and H2O. When this content reaches the colon, more potassium is secreted than usual.

Key learning 2: the increased luminal content needs to be released (lol), which leads to a hypovolaemia, hypochloraemia, metabolically acidotic, HYPOKALAEMIC patient.

Sexy bonus learning 1: hypovolaemia > lactic acidosis and/or secondary hyperaldosteronism sometimes, read vomiting section.

Renal Losses

Renal losses include mineralocorticoids, RTA, renal transport defects, hypomagnesaemia, and (most) diuretics. 

• Mineralocorticoid excess
• Aldosterone upregulates ENaC expression. ENaC is a luminal channel found in the late DCT, and throughout the collecting ducts. It causes transport of filtrate sodium into the tubular cell.
• Aldosterone also upregulates ROMK expression, a luminal channel found in the thick ascending limb, DCT, and collecting ducts.
• Sodium enters the cell from filtrate via ENaC. This changes the cell's voltage gradient, and forces potassium out of the cell into the filtrate via ROMK.
• Cortisol and aldosterone have ~equal affinities to the mineralocorticoid receptor. However, the presence of 11-beta-hydroxysteroid dehydrogenase type 2 in the kidney sees cortisol converted to cortisone which has only about 1% the affinity for mineralocorticoid receptors. Please note that hypercortisolism can still lead to hypokalaemia via this mechanism if levels are high enough.

• Renal tubular acidosis (types 1 and 2 only)
• Type 1 (distal RTA): failure to secrete protons in the alpha-intercalated cells of the late DCT and collecting ducts. Basically K+/H+ ATPase normally resorbs K+ while secreting H+. If this does not happen, potassium is left in the filtrate to be excreted from the body.
• Type 2 (proximal RTA): failure to absorb bicarbonate in the PCT. As a result, you do not resorb NaHCO3, and the urine is very salty. Very salty urine gets to the macula densa, leading to aldosterone secretion, leading to an upregulation of ENaC and ROMK. This results in an attempt to save as much sodium, thereby dumping as much potassium as possible, at the level of the DCT. Thus, hypokalaemia.
• Bonus learning: NSAIDs classically may cause hyperkalaemia - however, propionic acid derivatives (a subclass of NSAIDs) may cause RTA (likely type 1), leading to hypoK.

• Hypomagnesaemia
• Magnesium regulates the activity of ROMK. Normal intracellular levels of magnesium block ROMK, preventing "back-leak" of potassium through the channel. When levels are low, it is hypothesised that ROMK allows a potassium efflux (more information here).

• Diuretics
• Osmotic diuretics, i.e. mannitol: osmotic drag causes electrolytes to follow into filtrate.
• Carbonic anhydrase inhibitors, i.e. acetazolamide: inhibition of carbonic anhydrase II in PCT cells prevents conversion of CO2 + H2O into HCO3- and H+. This prevents resorption of sodium as NaHCO3 and thereby increases the salinity of filtrate, causing secondary hyperaldosteronism.
• Loop diuretics, i.e. furosemide: there is usually a Na+/K+/2Cl- inbound luminal cotransporter in the thick ascending limb of the nephron. Furosemide deactivates this cotransporter. This causes greater delivery of sodium to the DCT and beyond, which ENaC will absorb, and ROMK will excrete potassium to maintain voltage gradient. Furosemide also causes secondary hyperaldosteronism, which exacerbates the hypokalaemia, and ironically can lead to hypernatraemia (see mineralocorticoid excess above).
• Thiazides: there is usually a Na+/Cl- inbound luminal cotransporter in the DCT. Thiazides deactivate this channel leading to sodium wastage after the macula densa. This still leads to secondary hyperaldosteronism as volume depletion can lead to sympathetic drive which can cause aldosterone release, thereby causing hypokalaemia (see mineralocorticoid excess again).

Generally, any natriuretic that is NOT potassium-sparing will cause hypokalaemia as increased sodium in the tubule will drive ENaC (Na+ IMPORT) activity, thereby driving ROMK (K+ EXPORT) activity.

Dialysis

Kind of a weird one - AAFP put this in the "abnormal losses" category (which is where I have put it), and the mechanism for that is self-explanatory. 

There is a paper from 1981 which describes a patient nearing death because of hypokalaemia following dialysis. However, it seems this was mainly because of a rapid correction of their slowly-acquired acidosis, which is in itself a cause of hypokalaemia (cells absorb potassium, excrete protons into plasma as a result of rapid change from a chronically-acquired acidotic baseline). 

Intracellular Uptake

Sometimes potassium likes to move around different compartments in your body. The sympathetic activity, insulin, and pH change sections will be very useful for the upcoming hyperkalaemia article.

Sympathetic Activity and Drugs

Increased sympathetic activity i.e. beta-2 agonists, sympathomimetic nasal decongestants, delirium tremens, head injury, myocardial ischaemia. Physiology as follows:

1. Brief extracellular shift by alpha-1 and alpha-2 agonism, via activation of hepatic calcium-dependent potassium outbound channels.
2. Later intracellular shift by beta-1 and beta-2 receptor agonists by activation of Na+/K+ ATPase in skeletal muscle and liver.
3. Beta-3 receptor agonists may also drive intracellular shift.

Insulin

Most often clinically relevant when treating DKA, otherwise in the management of T1/T2DM, overdose, and in refeeding syndrome. Insulin activates the Na+/K+ ATPase pump. It also allows intake of glucose into the cell via GLUT4, which will eventually be a fuel source to maintain the action of the pump. This drives potassium intracellularly, which can leave the serum deplete.

At presentation, most patients with untreated DKA will have a normal or high serum potassium. This is partially because of low Na+/K+ ATPase activity (meaning cells are deplete but serum is not) but also because of metabolic acidosis. Consider renal comorbidities too.

pH Changes

Alkalosis is a lack of H+ in the serum (pH = -log[H+]). Briefly:

• Systemically, our cells will buffer alkalosis by releasing protons into the extracellular space in exchange for intake of potassium. This drives hypokalaemia.
• Alpha-intercalated cells of the DCT and collecting ducts will decrease their K+/H+ ATPase (K+ into cell / H+ into lumen) and H+ ATPase (H+ into lumen) activity. This leads to more potassium excreted in urine.
• Beta-intercalated cells increase Pendrin activity to absorb Cl- and excrete HCO3-. Sodium follows this HCO3- into the filtrate and is absorbed by ENaC channels, leading to potassium excretion by ROMK channels (principal cells).

Thyrotoxicosis

Thyroid hormones have a permissive effect on catecholamines, i.e. T3 increases the effects of adrenaline and noradrenaline on tissue. If you have supraphysiological levels of thyroid hormone, sympathetic stimulation is significantly enhanced. Sympathetic stimulation increases Na+/K+ ATPase activity, resulting in intracellular potassium shift.

Hypothermia

Hypothermic hypokalaemia is complicated and poorly understood. Some existing theories are:

• Hypothermia results in a sympathetic response which itself increases the activity of Na+/K+ ATPase, resulting in an intracellular shift of potassium.
• Potassium pools in the liver because while the sympathetic response will decrease insulin production, insulin has already accumulated in the liver, acting on hepatocytes to sink potassium. 
• Specialised temperature-sensitive K+ channels might exist?

The main important thing here is just to consider that correction of hypothermic hypokalaemia by administration of potassium may cause refractory hyperkalaemia when that patient is rewarmed.

Also, hyperkalaemia in hypothermia can be an indicator of bad prognosis (may be an indicator of cell lysis, which could be due to hypothermia itself or other causes i.e. concomitant hypoxia).

Refeeding Syndrome

When a person ceases eating, insulin secretion will decrease and glucagon secretion will increase. After approximately the first day of fasting, glycogenolysis in the liver and skeletal muscle will cease and a shift to lipolysis and gluconeogenesis occurs.

Basal metabolic rate drops due to reduced activity in peripheral type 1 deiodinase (the enzyme responsible for T4 to T3 conversion). Additionally, Na+/K+ ATPase is downregulated in the absence of insulin. This changes the handling of electrolytes such as potassium, magnesium, and phosphate, shifting intracellular stores extracellularly and losing them in urine. When combined with no oral intake, total body stores drop.

Please also consider that thiamine (Vit B1) may be deficient in the patient. Sudden reintroduction of energy substrate without thiamine administration in the deficient patient may result in Wernicke-Korsakoff syndrome.

Note that prior to refeeding, serum phosphate, magnesium, and potassium may be normal due to the aforementioned intracellular to extracellular shift, which masks depleted intracellular stores.

The danger occurs when food is reintroduced. Glucose intake causes insulin release, which sees ATP (and 2,3DPG, haeme nerds) production increase, thus driving down serum phosphate. Activation of Na+/K+ ATPase by insulin and fuel from glucose forces potassium back into cells, dropping serum potassium. Exactly how hypomagnesaemia develops is unclear but is likely also an intracellular shift for use in enzymes.

Earlier I discussed how hypomagnesaemia causes hypokalaemia. Think about how this interacts with a patient's physiology in refeeding syndrome.

I also discussed how metabolic alkalosis can cause hypokalaemia. Think about the mechanism - can hypokalaemia cause alkalosis? Yes!

Pseudohypokalaemia

Occasionally found in samples from patients with absurdly high WCC (i.e. >75-100 * 10^9/L) - remember that the normal range is ~4-11 * 10^9/L. A proposed mechanism for this is that leukaemic leukocytes have an increased sodium permeability which leads to increased Na+/K+ ATPase activity, and the white cells slurp the potassium out of the tube. This can be avoided by separating the serum or plasma (not the same thing, by the way) from the blood sample quickly.

Treating HypoK

I am obligated to remind you that I am not a doctor - I am a fourth year medical student at the time of writing this. While I strive to provide accurate and up-to-date information, information on this site is not medical advice, and I cannot guarantee the completeness, accuracy, or reliability of the content.

To avoid trouble, click for the QLD Electrolyte Guidelines. These guidelines may not apply where you practise.