INTRODUCTION — Hypokalemia is a common clinical problem. Potassium enters the body via oral intake or intravenous infusion, is largely stored in the cells, and then excreted in the urine. Thus, decreased intake, increased translocation into the cells, or, most often, increased losses in the urine, gastrointestinal tract, or sweat can lead to a reduction in the serum potassium concentration (table 1).
This topic will review the major causes of hypokalemia. The evaluation and treatment of hypokalemia are discussed separately. (See "Evaluation of the adult patient with hypokalemia" and "Clinical manifestations and treatment of hypokalemia in adults".)
DECREASED POTASSIUM INTAKE — Potassium intake is normally 40 to 120 mEq per day, most of which is then excreted in the urine. The kidney is able to lower potassium excretion to a minimum of 5 to 25 mEq per day in the presence of potassium depletion . Thus, decreased intake alone rarely causes significant hypokalemia. This was demonstrated in a study of normal individuals in whom lowering potassium intake to 20 mEq per day was associated with a reduction in serum potassium from 4.1 mEq/L at baseline to 3.5 mEq/L .
However, a low potassium intake can contribute to the severity of potassium depletion when another cause of hypokalemia is superimposed, such as diuretic therapy.
INCREASED ENTRY INTO CELLS — More than 98 percent of total body potassium is intracellular, chiefly in muscle [3,4]. The normal distribution of potassium between cells and the extracellular fluid is primarily maintained by the Na-K-ATPase pump in the cell membrane [3,4]. Increased activity of the Na-K-ATPase pump and/or alterations in other potassium transport pathways can result in transient hypokalemia due to increased potassium entry into cells.
Increased availability of insulin — Insulin promotes the entry of potassium into skeletal muscle and hepatic cells, predominantly by increasing the activity of the Na-K-ATPase pump . This effect is most prominent after the administration of exogenous insulin to patients with diabetic ketoacidosis or severe nonketotic hyperglycemia who are often normokalemic or hyperkalemic at presentation, even though they have lost potassium . Hypokalemia can rarely result from an insulin overdose . (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Treatment", section on 'Potassium replacement'.)
Endogenous insulin released in response to a carbohydrate load may also contribute to hypokalemia. This has been described in patients with refeeding syndrome  and after the administration of intravenous potassium in a dextrose in water solution. Thus, initial intravenous potassium therapy for hypokalemia should be given in a saline rather than dextrose solution. This issue is discussed in detail elsewhere. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Intravenous potassium repletion'.)
Elevated beta-adrenergic activity — Endogenous catecholamines, acting via beta-2 adrenergic receptors [4,8], can promote potassium entry into cells by increasing the activities of the Na-K-ATPase pump  and the Na-K-2Cl (NKCC1) cotransporter  and possibly by increasing the release of insulin . A proposed physiologic role for this effect of increased beta-2 adrenergic activity is to moderate the acute hyperkalemia of exercise .
As a result of potassium flux into cells, transient hypokalemia can develop in any setting in which there is stress-induced release of epinephrine, including alcohol withdrawal [3,13], acute myocardial infarction [3,14], head injury , or theophylline intoxication [16,17].
Similar effects, in which the serum potassium concentration can fall acutely by more than 0.5 to 1 mEq/L, have been observed in the following settings:
●Exposure to heroin or meats contaminated with the beta-adrenergic agonist, clenbuterol 
Regardless of the cause of increased beta-adrenergic activity, the degree of hypokalemia will be greater in patients with preexisting hypokalemia due, for example, to diuretic therapy (figure 1) . (See 'Diuretics' below.)
This potassium-lowering effect of beta agonists may be particularly likely to induce arrhythmias in the following settings:
●In women with preterm labor. One study, for example, found that 3 of 14 patients treated with either ritodrine or terbutaline for the prevention of preterm labor developed a symptomatic arrhythmia, such as supraventricular tachycardia or premature atrial complex (PAC; also referred to a premature atrial beat, premature supraventricular complex, or premature supraventricular beat) and premature ventricular beats .
In addition, beta agonists can be given acutely to treat severe hyperkalemia. On the other hand, nonselective beta blockers can raise the serum potassium, particularly if given with a potassium load (figure 2). (See "Treatment and prevention of hyperkalemia in adults", section on 'Beta-2-adrenergic agonists' and "Causes and evaluation of hyperkalemia in adults", section on 'Beta blockers' and "Causes and evaluation of hyperkalemia in adults", section on 'Exercise'.)
Elevated extracellular pH — Either metabolic or respiratory alkalosis can promote potassium entry into cells. In the presence of alkalemia, hydrogen ions leave the cells to minimize the increase in extracellular pH; the necessity to maintain electroneutrality then requires the entry of some potassium (and sodium) into the cells. The serum potassium concentration falls by less than 0.4 mEq/L for every 0.1 unit rise in pH .
In addition to alkalemia leading to cellular potassium uptake, metabolic alkalosis is a common finding in hypokalemia, primarily because the major causes of hypokalemia (such as diuretics, vomiting, and hyperaldosteronism, described below) also lead to losses of hydrogen ions. Hypokalemia is an important cofactor in the maintenance of metabolic alkalosis since it promotes bicarbonate reabsorption, thereby impairing correction of the alkalemia by excretion of the excess bicarbonate (figure 3). (See "Pathogenesis of metabolic alkalosis", section on 'Hypokalemia' and "Treatment of metabolic alkalosis".)
Hypokalemic periodic paralysis — Hypokalemic periodic paralysis is a rare neuromuscular disorder characterized by potentially fatal episodes of muscle weakness or paralysis that can affect the respiratory muscles. It may be hereditary, with an autosomal dominant mode of inheritance, or acquired in patients with hyperthyroidism. Acute attacks, in which the sudden movement of potassium into the cells can reduce the serum potassium to as low as 1.5 to 2.5 mEq/L, are often precipitated by rest after exercise, stress, or a carbohydrate meal. The serum potassium is normal during periods between the recurrent attacks of paralysis, a characteristic which can help distinguish periodic paralysis from other forms of hypokalemic paralysis. Patients with hypokalemic periodic paralysis will also have a low urinary excretion of potassium; this finding can help distinguish these patients from those who have hypokalemic paralysis due to renal loss of potassium . (See "Hypokalemic periodic paralysis" and "Thyrotoxic periodic paralysis".)
Paradoxical hypokalemia after repletion — Some patients with either periodic or nonperiodic hypokalemia can develop worsening, "paradoxical" hypokalemia after potassium repletion. In a cohort of 78 patients with thyrotoxic periodic paralysis, for example, the serum potassium decreased (rather than increased) by a mean of 0.4 mEq/L in 20 patients . These patients with paradoxical hypokalemia had higher thyroxine concentrations, required more potassium chloride supplementation to reverse symptoms of hypokalemia, and had more pronounced rebound hyperkalemia posttreatment. High thyroxine levels may produce a more exaggerated potassium uptake in these patients, resulting in paradoxical hypokalemia.
The mechanism of paradoxical hypokalemia is likely different in patients with nonperiodic hypokalemia. In a cohort of 58 such patients, paradoxical hypokalemia developed in 30 . Correlates of paradoxical hypokalemia included higher urinary potassium excretion rates, higher renin levels, and higher volumes of saline resuscitation.
Increased blood cell production — An acute increase in hematopoietic cell production is associated with potassium uptake by the new cells and this may lead to hypokalemia. Administration of vitamin B12 or folic acid to treat a megaloblastic anemia or use of granulocyte-macrophage colony-stimulating factor (GM-CSF) to treat neutropenia are the most common scenarios in which this occurs [28-30].
A similar mechanism may lead to spurious hypokalemia in blood samples drawn from patients with many metabolically active blood cells, such as patients with acute myeloid leukemia and a high white blood cell count . If the blood is allowed to stand at room temperature prior to measurement of the potassium concentration, the measured value may be below 1 mEq/L even though the patient is without symptoms, signs, or sequelae of hypokalemia. This spurious hypokalemia can be prevented by either rapid separation of the plasma from the cells following venipuncture, or storage of the blood at 4°C before assay. (See "Overview of the complications of acute myeloid leukemia", section on 'Hypokalemia'.)
Hypothermia — Accidental or induced hypothermia can drive potassium into the cells and lower the serum potassium concentration to 3.0 to 3.5 mEq/L or less [32,33]. By contrast, hypothermic patients who are unresponsive to resuscitation may have marked preterminal hyperkalemia, due to irreversible tissue necrosis .
Barium intoxication — Barium intoxication, which usually results from the ingestion of contaminated food or from a suicide attempt , can cause hypokalemia by blocking the potassium channels in the cell membrane that normally allow cellular potassium to diffuse into the extracellular fluid . Treatment of barium poisoning with potassium replacement serves to both increase the serum potassium concentration and to displace barium from affected potassium channels . Hemodialysis is also an effective treatment .
Patients undergoing radiographic procedures are not at risk for this complication since the barium sulfate used in these studies does not enter the systemic circulation.
Cesium intoxication — Cesium intoxication, usually due to the use of cesium chloride as an alternative therapy for cancer, can be associated with hypokalemia . How this occurs is unclear, but may result from cesium blockade of membrane potassium channels .
Chloroquine intoxication — Hypokalemia, with the serum potassium concentration falling below 2.0 mEq/L in severe cases, is a common finding in acute chloroquine intoxication . This effect is presumably mediated by potassium movement into the cells and can be exacerbated by the administration of epinephrine to help treat the intoxication.
INCREASED GASTROINTESTINAL LOSSES — Loss of gastric or intestinal secretions from any cause (vomiting, diarrhea, laxatives, or tube drainage) is associated with potassium losses and, possibly, hypokalemia .
Upper gastrointestinal losses — The concentration of potassium in gastric secretions is only 5 to 10 mEq/L; thus, potassium depletion in this setting is primarily due to increased urinary losses .
The following sequence is responsible for the urinary potassium loss with removal of gastric acid. The associated metabolic alkalosis and rise in plasma bicarbonate concentration increases the filtered bicarbonate load above its reabsorptive threshold. As a result, more sodium bicarbonate and water are delivered to the distal potassium secretory site. In combination with a hypovolemia-induced increase in aldosterone release, the net effect is increased potassium secretion and potentially large urinary potassium losses. Because of inappropriate sodium wasting with bicarbonate, a low urine chloride concentration is used to detect the presence of volume depletion. (See "Clinical manifestations and evaluation of metabolic alkalosis".)
The urinary potassium wasting seen with loss of gastric secretions is typically most prominent in the first few days; thereafter, bicarbonate reabsorptive capacity increases, leading to a marked reduction in urinary sodium, bicarbonate, and potassium losses . At this time, the urine pH falls from above 7.0 (due to bicarbonate wasting) to below 6.0.
Lower gastrointestinal losses — In contrast to gastric secretions, the potassium concentration in lower intestinal losses is relatively high (20 to 50 mEq/L) in most cases. In addition, hypokalemia due to lower gastrointestinal tract losses (usually from diarrhea) are typically associated with bicarbonate wasting and hyperchloremic metabolic acidosis rather than the metabolic alkalosis observed with upper gastrointestinal losses. However, some patients with hypokalemia due to factitious diarrhea or surreptitious laxative abuse develop metabolic alkalosis via an uncertain mechanism. (See "Factitious diarrhea: Clinical manifestations, diagnosis, and management", section on 'Clinical manifestations'.)
Hypokalemia from lower gastrointestinal losses is most common when the losses occur over a prolonged period, as with a villous adenoma, a vasoactive intestinal peptide secreting tumor (VIPoma), or with persistent infectious diarrhea [41-43]. In many cases, increased fecal losses cannot explain the entire potassium deficit. Since most people ingest an average of 80 mEq of potassium per day and urinary potassium excretion should fall below 15 to 25 mEq/day in the presence of hypokalemia , fecal losses (which are normally approximately 10 mEq/day) must exceed 55 to 65 mEq/day to directly induce hypokalemia. However, many patients with diarrhea who become hypokalemic have fecal potassium excretion below this level, indicating that other factors, such as decreased intake and volume depletion with increased aldosterone activity, must also play a contributory role . (See 'Increased urinary losses' below.)
Other causes of hypokalemia due to lower gastrointestinal losses have been described. These include:
●Bowel cleansing for colonoscopy with both sodium phosphate (which is now infrequently used) and polyethylene-glycol (PEG)-based preparations, particularly among older adults [45,46]. (See "Acute phosphate nephropathy".)
●Acute colonic pseudo-obstruction (Ogilvie's syndrome), which is associated with a secretory diarrhea characterized by an abnormally high potassium content due to activation of colonic potassium secretion. (See "Acute colonic pseudo-obstruction (Ogilvie's syndrome)", section on 'Clinical manifestations'.)
●Ingestion of clay ("geophagia"), which binds potassium in the gastrointestinal tract [47-49].
INCREASED URINARY LOSSES — Urinary potassium excretion is derived mostly from the secretion of potassium in the distal nephron, particularly by the principal cells in the connecting tubule and cortical collecting tubule [3,50]. Hypokalemia due to increased urinary losses is primarily due to two factors [44,51]:
●Increased mineralocorticoid activity – Aldosterone acts mainly by stimulating sodium reabsorption via the epithelial sodium channel (ENaC). Reabsorption of cationic sodium makes the lumen relatively electronegative, thereby promoting passive potassium secretion from the tubular cell into the lumen through potassium channels (eg, ROMK) in the luminal membrane (figure 4).
●Increased distal delivery of sodium and water – Enhanced potassium secretion can result from increased delivery of sodium to the collecting tubule, particularly if accompanied by nonreabsorbable anions rather than chloride. (See 'Nonreabsorbable anions' below.)
Potassium wasting can also result from polyuria as seen, for example, in primary polydipsia. In this setting, the urine potassium concentration is appropriately low (less than 15 mEq/L), but cumulative potassium excretion may be greater than intake due to the marked increase in urine volume. (See 'Polyuria' below.)
In most patients, increases in both mineralocorticoid activity and distal flow are present concurrently (eg, diuretic therapy, primary aldosteronism). If only one parameter is increased, the other must be normal to permit excessive loss of potassium. This important concept is illustrated by the absence of hypokalemia in patients who have a compensatory increase in aldosterone due to volume depletion. In such cases, angiotensin II stimulates sodium reabsorption in the proximal and distal tubules, which indirectly reduces distal sodium and water delivery. Angiotensin II also inhibits potassium secretory channels in the collecting tubule [50,52,53], thereby counterbalancing the stimulatory effect of aldosterone on potassium secretion.
In response to hypokalemia due to increased but stable urinary losses, urinary potassium excretion eventually falls to a value equivalent to potassium intake. At this point, the serum potassium is low but will not fall further unless potassium wasting forces increase due, for example, to an increase in diuretic dose or in aldosterone secretion in primary aldosteronism.
This adaptive response to hypokalemia results in part from reduction in the activity of the potassium secretory (eg, ROMK) channels in the luminal membrane of the cortical collecting tubule (figure 4), an effect that is potentially mediated by increased angiotensin II activity [50,54,55]. As an example, downregulation of luminal potassium channels will minimize the degree of hypokalemia seen in patients with primary aldosteronism and may explain why hypokalemia is an inconsistent finding in this disorder. (See "Pathophysiology and clinical features of primary aldosteronism", section on 'Hypokalemia: An inconsistent finding'.)
Major causes of urinary potassium wasting — The most common causes of hypokalemia due to urinary potassium losses include diuretic use, a primary increase in mineralocorticoid activity, increased distal delivery of nonreabsorbable anions, and loss of gastric secretions.
Diuretics — Any diuretic that acts proximal to the potassium secretory site – carbonic anhydrase inhibitors (eg, acetazolamide), loop diuretics, and thiazide-type diuretics – will both increase distal delivery and, via the induction of volume depletion, activate the renin-angiotensin-aldosterone system. As a result, urinary potassium excretion will increase, leading to hypokalemia if the urinary losses are greater than intake.
The incidence and severity of hypokalemia are dose dependent, occurring much less frequently with lower doses [56,57]. Thus, lower doses of thiazides (eg, 12.5 to 25 mg/day of chlorthalidone or hydrochlorothiazide) are now widely used in the treatment of hypertension because they are as effective in blood pressure reduction (figure 5) with a lesser effect on electrolyte balance (figure 6) . In two large hypertension trials of low-dose chlorthalidone, hypokalemia requiring therapy occurred in 7 to 8 percent of patients [59,60]. (See "Use of thiazide diuretics in patients with primary (essential) hypertension" and "Loop diuretics: Dosing and major side effects".)
Overall, hypokalemia is more frequent with thiazide diuretics than with loop diuretics, despite having a less potent natriuretic effect [3,61,62]. One potential explanation is the differential effect on calcium excretion. Whereas thiazide diuretics decrease calcium excretion , loop diuretics lead to a significant increase in calcium excretion . The higher luminal calcium concentration in the distal nephron produced by loop diuretics reduces the lumen-negative driving force for potassium excretion [65,66], thereby blunting their kaliuretic effect of loop diuretics.
In stable patients on a fixed diuretic dose, potassium loss, like other diuretic-induced fluid and electrolyte complications, occurs only during the first two weeks of therapy before a new steady state is established (figure 7). Thus, a stable patient with a normal serum potassium concentration at three weeks is not at risk of late hypokalemia unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced. (See "Time course of loop and thiazide diuretic-induced electrolyte complications".)
Once a steady state is reached, further monitoring is not required, unless the diuretic dose is increased, extrarenal potassium losses increase, or dietary potassium intake is reduced. As an example, increased losses and decreased intake may be seen with gastroenteritis. In such patients, temporary cessation of diuretic therapy for a few days may be appropriate.
In patients with hypertension who develop diuretic-induced hypokalemia, either another agent can be used, or the hypokalemia can be treated with a potassium-sparing diuretic or potassium supplementation. (See "Clinical manifestations and treatment of hypokalemia in adults", section on 'Treatment'.)
Increased mineralocorticoid activity — Urinary potassium wasting is characteristic of any condition associated with primary hypersecretion of a mineralocorticoid, as with an aldosterone-producing adrenal adenoma. These patients are usually hypertensive, and the differential diagnosis includes diuretic therapy (which may be surreptitious) in a patient with underlying hypertension, and renovascular disease, in which increased secretion of renin leads to enhanced aldosterone release. (See "Pathophysiology and clinical features of primary aldosteronism" and "Diagnosis of primary aldosteronism".)
Increased mineralocorticoid activity with suppressed circulating aldosterone concentrations (called apparent mineralocorticoid excess) is an uncommon condition due to autosomal recessive, loss-of-function mutations in the 11β-hydroxysteroid dehydrogenase-2 (11-betaHSD2) gene or to inhibition of this enzyme due to chronic licorice ingestion or use of antifungal agents (itraconazole and posaconazole) [67-69]. (See "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)
The anti-androgen drug abiraterone, which is used to treat prostate cancer, can also cause apparent mineralocorticoid excess with hypokalemia and hypertension [70,71], albeit through a different mechanism than 11-betaHSD2 inhibition. Abiraterone inhibits the CYP17A1 enzyme, 17-alpha hydroxylase, decreases cortisol, and increases plasma corticotropin (ACTH) . Increased ACTH leads to the generation of excessive amounts of deoxycorticosterone, which has potent mineralocorticoid effects, causing hypokalemia and hypertension. This ACTH-dependent mineralocorticoid excess can be mitigated by coadministration of glucocorticoids with abiraterone [71,73], use of mineralocorticoid receptor antagonists, or salt restriction .
Nonreabsorbable anions — The lumen-negative electrical gradient created by sodium reabsorption in the cortical collecting tubule is partially attenuated by chloride reabsorption. There are, however, a number of clinical settings in which sodium is presented to the distal nephron with relatively large quantities of a nonreabsorbable anion, including bicarbonate with vomiting or proximal renal tubular acidosis, beta-hydroxybutyrate in diabetic ketoacidosis, hippurate following toluene use (glue sniffing), or a penicillin derivative in patients receiving high-dose penicillin therapy. In these settings, more of the delivered sodium will be reabsorbed in exchange for potassium, leading to a potentially marked increase in potassium excretion [75,76]. As an example, the serum potassium concentration is below 2 mEq/L in approximately one-fourth of patients with toluene-induced metabolic acidosis . (See "The delta anion gap/delta HCO3 ratio in patients with a high anion gap metabolic acidosis", section on 'D-lactic acidosis and toluene inhalation'.)
The effect of nonreabsorbable anions is likely to be most prominent when there is concurrent volume depletion. In this setting, the decrease in distal chloride delivery (thereby limiting the ability of chloride reabsorption to dissipate the lumen-negative gradient) and the enhanced secretion of aldosterone both promote potassium secretion . In diabetic ketoacidosis, for example, increased distal sodium and water delivery (due to the glucose osmotic diuresis), hypovolemia-induced hyperaldosteronism, and beta-hydroxybutyrate acting as a nonreabsorbable anion all can contribute to potassium wasting . (See "Diabetic ketoacidosis and hyperosmolar hyperglycemic state in adults: Clinical features, evaluation, and diagnosis", section on 'Serum potassium'.)
Loss of gastric secretions — The mechanism by which loss of gastric secretions leads to urinary potassium wasting is described above, in which there is an increase in sodium bicarbonate delivery to the collecting tubule. This problem is usually apparent from the history. If, however, the history is not helpful, the differential diagnosis of a normotensive patient with hypokalemia, urinary potassium wasting, and metabolic alkalosis includes surreptitious vomiting, as well as diuretic use and Bartter syndrome. (See "Clinical manifestations and evaluation of metabolic alkalosis", section on 'Diagnostic approach in unexplained metabolic alkalosis'.)
Less common causes of urinary potassium wasting — Less common causes of hypokalemia due to urinary losses include a variety of acquired and genetic disorders.
Polyuria — Potassium-depleted subjects can normally reduce the urine potassium concentration to a minimum of 5 to 10 mEq/L . If, however, the urine output is over 5 to 10 L/day, then obligatory potassium losses can exceed 50 to 100 mEq per day. This problem is most likely to occur in primary (often psychogenic) polydipsia, in which the urine output may be elevated over a prolonged period of time . An equivalent degree of polyuria can also occur in arginine vasopressin deficiency (previously called central diabetes insipidus), but patients with this disorder typically seek medical care soon after the polyuria has begun.
Renal tubular acidosis — Potassium wasting can occur in both distal (type 1) and proximal (type 2) renal tubular acidosis. In each of these disorders, the degree of potassium depletion is masked by the tendency of acidemia to promote potassium movement out of the cells. Thus, the serum potassium concentration is higher than it should be in relation to the degree of potassium depletion. In some patients, the serum potassium concentration is normal or even elevated, although correction of the acidemia will uncover the true state of potassium balance. (See "Overview and pathophysiology of renal tubular acidosis and the effect on potassium balance" and "Potassium balance in acid-base disorders".)
Prior to treatment with bicarbonate, patients with a proximal renal tubular acidosis usually demonstrate mild hypokalemia, due primarily to baseline hyperaldosteronism . However, treatment with sodium bicarbonate to correct the acidemia increases distal tubular sodium and bicarbonate delivery, which can cause a marked increase in renal potassium wasting . (See "Treatment of distal (type 1) and proximal (type 2) renal tubular acidosis", section on 'Proximal (type 2) renal tubular acidosis'.)
Hypomagnesemia — Hypomagnesemia is present in up to 40 percent of patients with hypokalemia . In many cases, as with diuretic therapy, vomiting, diarrhea, or certain tubular toxins such as gentamicin and iphosphamide [3,81], there are concurrent potassium and magnesium losses.
However, hypomagnesemia can itself lead to increased urinary potassium losses via an uncertain mechanism, possibly involving an increase in the number of open potassium channels [82,83]. This mechanism, as well as the causes of hypomagnesemia, is discussed separately. (See "Hypomagnesemia: Clinical manifestations of magnesium depletion", section on 'Hypokalemia' and "Hypomagnesemia: Causes of hypomagnesemia".)
Determining whether hypomagnesemia is present is important clinically because the hypokalemia often cannot be corrected until the magnesium deficit is reversed .
Amphotericin B — Hypokalemia occurs in up to one-half of patients treated with amphotericin B . Amphotericin interacts with membrane sterols, leading to an increase in membrane permeability that can promote potassium secretion across the luminal membrane. Concurrent distal renal tubular acidosis may play a contributory role. (See "Amphotericin B nephrotoxicity".)
Salt-wasting nephropathies — Kidney diseases associated with decreased proximal, loop, or distal sodium reabsorption can infrequently lead to hypokalemia via a mechanism similar to that induced by diuretics. This problem can be seen with Bartter or Gitelman syndrome, tubulointerstitial diseases (such as reflux nephropathy or interstitial nephritis due to Sjögren's disease), hypercalcemia, tubular injury due to drugs such as cisplatin, and tubular injury that may be induced by lysozyme in patients with leukemia, particularly acute monocytic or myelomonocytic leukemia [3,28,85-87]. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations" and "Overview of the complications of acute myeloid leukemia".)
Liddle's syndrome — In patients with Liddle's syndrome, an autosomal dominant, gain-of-function mutation in ENaC leads to hereditary hypokalemia and hypertension, mimicking the syndrome of mineralocorticoid excess. (See "Genetic disorders of the collecting tubule sodium channel: Liddle syndrome and pseudohypoaldosteronism type 1", section on 'Liddle syndrome' and "Apparent mineralocorticoid excess syndromes (including chronic licorice ingestion)".)
Bartter and Gitelman syndromes — Mutations in a variety of tubular transport proteins can mimic the effects of chronic therapy with loop diuretics (Bartter syndrome) or thiazide diuretics (Gitelman syndrome), resulting in hypokalemia and metabolic alkalosis. (See "Inherited hypokalemic salt-losing tubulopathies: Pathophysiology and overview of clinical manifestations".)
Low-calorie diets — Ingestion of low-calorie diets (200 and 800 kcal/day) can result in hypokalemia, particularly in patients who do not consume supplementary potassium or who have an underlying predisposition to renal potassium wasting such as primary aldosteronism in which many patients are normokalemic at baseline [88-90]. These diets, intended to produce rapid weight loss, are usually carbohydrate poor and protein rich, such as the Atkins diet. (See "Obesity in adults: Dietary therapy", section on 'Low-carbohydrate diets' and "Ketogenic dietary therapies for the treatment of epilepsy".)
The mechanism of the hypokalemia in patients consuming low-calorie diets is not completely understood. Urinary potassium wasting is thought to be important since patients with obesity demonstrate a significant kaliuresis over the first two weeks of fasting or ingesting a low-carbohydrate diet . The kaliuresis may be due at least in part to the ketogenesis that results from a decrease in carbohydrate intake. As noted above, increased urinary excretion of ketoacid anions can increase urinary potassium excretion. (See 'Nonreabsorbable anions' above.)
INCREASED SWEAT LOSSES — Daily sweat losses are normally negligible since the volume is low and the potassium concentration is only 5 to 10 mEq/L. However, individuals exercising in a hot climate can produce 10 L or more of sweat per day, leading to potassium depletion if these losses are not replaced . Significant loss of potassium in sweat can also occur in cystic fibrosis . Urinary potassium excretion may contribute to the hypokalemia associated with increased sweat loss since aldosterone release is enhanced by exercise (via catecholamine-induced renin secretion) [92,94].
DIALYSIS — Although patients with end-stage kidney disease typically retain potassium and tend to be mildly hyperkalemic, hypokalemia can be induced in some patients by maintenance dialysis. As an example, dialysis potassium losses can reach 30 mEq per day in patients on chronic peritoneal dialysis. This can become clinically important if intake is reduced or if there are concurrent gastrointestinal losses . However, mild hypokalemia immediately following a session of hemodialysis is expected and should not be treated with potassium supplementation.
A different mechanism may be operative in patients treated with hemodialysis who have underlying potassium depletion. In this setting, the metabolic acidosis induced by kidney failure can result in a relatively normal predialysis serum potassium concentration due to potassium movement out of the cells. However, the high flows attained during hemodialysis can rapidly correct the acidemia, leading to potassium entry into cells and a potentially large reduction in the serum potassium concentration .
PLASMAPHERESIS — Plasmapheresis removes potassium in the same concentration as in the plasma. If, however, albumin is used as the replacement fluid, transient hypokalemia can be induced by dilution. This problem can be avoided by adding 4 mEq of potassium to each liter of albumin solution given. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Complications", section on 'Hypokalemia'.)
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Hypokalemia (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Hypokalemia is a common clinical problem that can result from decreased intake, increased translocation into the cells, or, most often, increased losses of potassium from the gastrointestinal tract or in the urine (table 1). (See 'Introduction' above.)
Potassium intake is normally 40 to 120 mEq per day. Since the kidney can reduce potassium excretion to 5 to 25 mEq per day in the presence of potassium depletion, decreased intake alone rarely causes hypokalemia. (See 'Decreased potassium intake' above.)
●Major causes of hypokalemia
•Translocation into cells – Total body potassium is predominantly intracellular, a distribution maintained principally by the Na-K-ATPase pump. Increased activity of the Na-K-ATPase and/or alterations in other potassium transport pathways can result in hypokalemia due to increased potassium entry into cells. Common examples of this phenomenon include (see 'Increased entry into cells' above):
-Increased insulin action (see 'Increased availability of insulin' above)
-Elevated beta-adrenergic activity (see 'Elevated beta-adrenergic activity' above)
-Elevated extracellular pH (see 'Elevated extracellular pH' above)
•Gastrointestinal loss – Loss of gastric or intestinal secretions from any cause (vomiting, diarrhea, laxatives, or tube drainage) is associated with potassium losses and, possibly, hypokalemia:
-Upper gastrointestinal losses (eg, vomiting) lead to hypokalemia through urinary potassium wasting. This occurs because the metabolic alkalosis resulting from gastric acid loss increases the filtered bicarbonate load above its reabsorptive threshold. As a result, more sodium bicarbonate and water are delivered to the distal potassium secretory site. (See 'Upper gastrointestinal losses' above.)
-In contrast to gastric secretions, the potassium concentration in lower intestinal losses is relatively high. Hypokalemia due to lower gastrointestinal tract losses (usually from diarrhea) are typically associated with bicarbonate wasting and metabolic acidosis rather than the metabolic alkalosis observed with upper gastrointestinal losses. Hypokalemia from lower gastrointestinal losses is most common when the losses occur over a prolonged period. (See 'Lower gastrointestinal losses' above.)
•Renal loss – Hypokalemia from urinary potassium wasting usually requires either mineralocorticoid excess (often from an increase in aldosterone) and/or an increase in distal flow. (See 'Increased urinary losses' above.)
The major causes of urinary potassium wasting include:
-Diuretics – Any diuretic that acts proximal to the potassium secretory site will both increase distal delivery and, via the induction of volume depletion, activate the renin-angiotensin-aldosterone system. (See 'Diuretics' above.)
-Increased mineralocorticoid activity – Urinary potassium wasting is characteristic of any condition associated with primary hypersecretion of a mineralocorticoid, as with an aldosterone-producing adrenal adenoma. (See 'Increased mineralocorticoid activity' above.)
-Excretion of nonreabsorbable anions – When sodium is delivered to the distal nephron with relatively large quantities of a nonreabsorbable anion, such as bicarbonate or beta-hydroxybutyrate, more of the delivered sodium will be reabsorbed in exchange for potassium, leading to a potentially marked increase in potassium excretion. (See 'Nonreabsorbable anions' above.)
●Other causes – Hypokalemia can occur in patients who sweat excessively, and in patients undergoing dialysis or plasmapheresis. (See 'Increased sweat losses' above and 'Dialysis' above and 'Plasmapheresis' above.)
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