Aetiology
The main causes of hypokalaemia are decreased potassium intake, increased potassium entry into cells, increased potassium excretion (e.g., from the GI tract, or through urine or sweat) and in special situations such as during dialysis or plasmapheresis.[2][Figure caption and citation for the preceding image starts]: Causes of increased potassium excretionFrom the collection of Sumit Sharma, University of Iowa [Citation ends].
Decreased potassium intake
It is rare for hypokalaemia to be caused by decreased potassium intake. However, this can happen if there is low potassium intake in conditions such as anorexia nervosa, during diuretic therapy, or with hypocaloric protein diets for rapid weight loss.[3]
Increased potassium entry into cells
This can occur by a number of mechanisms.
Elevation in extracellular pH: metabolic or respiratory alkalosis can facilitate potassium entry into cells (hydrogen ions leave the cells and potassium enters into cells to maintain electroneutrality). Administration of sodium bicarbonate to treat metabolic acidosis can also cause this phenomenon.
Increased beta-adrenergic activity: catecholamines promote potassium entry into the cells by increasing Na-K-ATPase activity.[4] Administration of a beta-adrenergic agonist such as salbutamol or terbutaline (e.g., to treat asthma or to prevent premature labour) or theophylline intoxication can also cause hypokalaemia.[5] Transient hypokalaemia may also occur during stress-induced release of adrenaline and cortisol (e.g., during acute illness or coronary ischaemia).[6]
Increased availability of insulin: insulin promotes the entry of potassium into skeletal muscle and hepatic cells by increasing the activity of the Na-K-ATPase pump.[4] This physiological action of insulin is more prominent after its administration in patients with diabetic ketoacidosis or hyperosmolar hyperglycaemic state.[7] The plasma concentration of potassium may also be reduced by a large carbohydrate load.
Hypokalaemic periodic paralysis: a rare disorder characterised by potentially fatal episodes of muscle weakness or paralysis that may affect the respiratory muscles. It can be precipitated by exercise, stress, or conditions associated with increased release of adrenaline, cortisol, aldosterone, or insulin.[8] Acute attacks can lower plasma potassium concentrations to 1.5 to 2.5 mmol/l (1.5 to 2.5 mEq/L) and are often accompanied by hypophosphataemia and hypomagnesaemia.[9] Excess thyroid hormone increases Na-K-ATPase activity and may predispose to paralytic episodes by increasing susceptibility to the hypokalaemic action of adrenaline or insulin.[10]
Increased blood cell production during anabolic states: increased potassium entry into cells may be caused by sharp increases in haematopoietic cell production that occurs with the use of granulocyte-macrophage colony-stimulating factor (GM-CSF) in neutropenia.[11] This may also occur after the administration of vitamin B12 or folic acid in megaloblastic anaemia.[11]
Chloroquine intoxication: hypokalaemia is a common finding in acute chloroquine intoxication.[12] This is caused by potassium movement into cells and can be exacerbated by the use of adrenaline to help treat the intoxication.
Hypothermia: there have been reports that hypothermia may result in a drive of potassium into cells associated with a plasma potassium concentration decrease to below 3.0 to 3.5 mmol/L (3.0 to 3.5 mEq/L).[13] This is reversible on re-warming. Supplementation of potassium during hypothermia can also cause a significant increase in serum potassium concentration on re-warming.[14]
Losses from the GI tract
Loss of gastric or intestinal secretions from any cause (vomiting, diarrhoea, laxatives, or tube drainage) can cause hypokalaemia.[11]
Vomiting: when severe or recurrent can also give rise to renal potassium loss in the setting of metabolic alkalosis.
Hypokalaemia from lower GI losses is most common when losses occur over a prolonged period, as with a villous adenoma or a vasoactive intestinal peptide secreting tumour (VIPoma).[15][16]
Ileal loop/conduit with ureteric implants: may lead to potassium losses.
Oral sodium phosphate solution: used for bowel cleansing and is associated with GI losses of potassium. This is more likely to occur in the elderly and those with decreased GI motility.[17]
Increased loss of potassium in urine
A wide variety of causes are associated with increased potassium loss in urine.
Diuretics (e.g., acetazolamide, loop diuretics, and thiazide-type diuretics): these increase the distal delivery of potassium and activate the renin-angiotensin-aldosterone system. Urinary potassium excretion increases and may lead to hypokalaemia if losses are not matched with potassium intake.
Mineralocorticoid excess: urinary potassium wasting is also characteristic of any condition associated with primary hypersecretion of mineralocorticoids (primary aldosteronism) or hypersecretion of catecholamines via enhanced release of renin. Apparent mineralocorticoid excess, characterised by oedema, hypertension, and hypokalaemia, occurs in disorders with congenital deficiency, or lack of renal 11-beta-hydroxysteroid dehydrogenase type 2 or its inhibition by chronic licorice ingestion, acute alcoholism, chronic liver or renal disease, pre-eclampsia, ectopic ACTH syndrome, and/or pregnancy-induced hypertension.[1][18][19][20][21][22][23][24] An uncommon cause of mineralocorticoid excess is congenital adrenal hyperplasia caused by 11-beta-hydroxylase deficiency.
Salt-wasting nephropathies: certain renal diseases associated with decreased proximal, loop, or distal sodium reabsorption can infrequently lead to hypokalaemia via a mechanism similar to that induced by diuretics. Bartter's or Gitelman's syndromes, tubulo-interstitial diseases (due to Sjögren's syndrome or lupus), and renal tubular injury in patients with leukaemia can also cause hypokalaemia by these mechanisms.[25][26][27][28]
Presence of non-reabsorbable anions: a marked increase in potassium excretion by reabsorbing sodium in exchange for potassium can occur during vomiting or type 2 renal tubular acidosis, or beta-hydroxybutyrate in diabetic ketoacidosis, or it may be drug-induced.[29][30] In these conditions a decrease in distal chloride delivery and the enhanced secretion of aldosterone also promote potassium secretion.[31]
Metabolic acidosis: potassium wasting occurs in both type 1 (distal) and type 2 (proximal) renal tubular acidosis. In each of these disorders the degree of potassium depletion is masked by the efflux of potassium out of the cells caused by acidaemia.
Amphotericin B: hypokalaemia occurs in up to one half of patients treated with amphotericin B.[32] Amphotericin increases membrane permeability, promoting potassium secretion across the luminal membrane but it can also cause concurrent type 1 renal tubular acidosis that may play a contributory role in hypokalaemia.
Hypomagnesaemia: serum magnesium <0.75 mmol/L (<1.5 mEq/L) present in up to 40% of patients with hypokalaemia.[33][34] Hypomagnesaemia can lead to increased urinary potassium loss via an uncertain mechanism, possibly involving an increase in the number of open potassium channels. The presence of hypocalcaemia is often a clue to underlying hypomagnesaemia. It is important to determine whether there is hypomagnesaemia because hypokalaemia can often only be corrected once the magnesium deficit has been addressed.[35]
Polyuria: this is most likely to occur in primary (often psychogenic) polydipsia in which the urine output may be elevated over a prolonged period of time.[36] Polyuria can also occur in central diabetes insipidus, although patients typically seek medical care soon after the polyuria begins.
Increased loss via sweating
Exercising in a hot climate can produce more than 10 L of sweat daily, leading to potassium depletion if losses are not replaced.[37]
Urinary potassium excretion may also contribute, since aldosterone release is enhanced both by exercise (via catecholamine-induced renin secretion) and volume loss.
Significant loss of potassium in sweat can also occur in patients with cystic fibrosis.[38]
Burns and other dermatological conditions (i.e., eczema or psoriasis involving a large surface area of the skin, especially with the use of topical steroids) can cause increased loss of potassium through the skin.
Miscellaneous
Chronic alcoholism is a common cause of hypokalaemia.[39] Hypokalaemia occurs for various reasons, such as poor oral intake, associated vomiting, and secondary hyperaldosteronism.
Hypokalaemia can be induced in some patients by maintenance dialysis. Potassium losses can reach up to 30 mmol/day (30 mEq/day) in patients on chronic peritoneal dialysis. This may become clinically important if potassium intake is reduced or if there are concurrent GI losses.[40]
Hypokalaemia can complicate plasmapheresis.[41] Albumin use as a replacement fluid can cause transient dilutional hypokalaemia.[42]
Liddle's syndrome is caused by a mutation that creates hyperactivity of the amiloride-sensitive sodium channel, leading to early-onset severe hypertension, hypokalaemia and metabolic alkalosis, with low plasma renin and low plasma aldosterone.[43]
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