Hypokalemia, or Low Potassium

Etiological Factors Associated With Hypokalemia

Causes of Hypokalemia

The accurate treatment of hypokalemia requires correct identification of the cause. Hypokalemia can be associated either with normal or decreased total body potassium content. Normal total body potassium with hypokalemia is a result of potassium redistribution from the extracellular to the intracellular space. Total body potassium depletion can result from either renal or extrarenal potassium losses. We suggest that the clinician evaluating a patient with hypokalemia consider four broad groups of etiologies: pseudohypokalemia, redistribution, extrarenal potassium loss, and renal potassium loss.

Pseudohypokalemia

Abnormal white blood cells, if present in large enough numbers, can take up extracellular potassium when stored for prolonged periods at room temperature, resulting in a low measured plasma potassium level. The apparent hypokalemia is an artifact of the storage procedure and is referred to as “pseudohypokalemia” . The most common underlying disease state is acute myelogenous leukemia. Rapid separation of the plasma or storing the sample at 4?C confirms the diagnosis, avoids this artifact, and prevents inappropriate treatment.

Redistribution

More than 98% of total body potassium is present in the intracellular fluid, predominantly in skeletal muscle cells, enabling small changes in the distribution of potassium to alter the extracellular concentration markedly. Certain hormones, particularly insulin, aldosterone, and sympathomimetics, are the most common cause of redistribution-induced hypokalemia. Insulin activates Na+ -K+ -ATPase, which results in active potassium uptake . Acute insulin administration produces rapid potassium shifts from the extra- to intracellular space, resulting in hypokalemia. This problem is most frequently encountered in the treatment of diabetic ketoacidosis. Insulin-induced redistribution of potassium is the physiologic principle underlying the administration of insulin with glucose to patients with hyperkalemia. In contrast to acute insulin administration, chronically high insulin levels, as occur in insulinomas, do not typically cause hypokalemia; the mechanism of this “escape” is unknown. The decreased end-organ responsiveness to insulin in adult-onset diabetes may contribute to the hyperkalemia frequently seen by altering the distribution of potassium between the intra- and extracellular space.

A second, clinically common cause of potassium redistribution is aldosterone. Aldosterone induces cellular uptake of potassium through a variety of effects, but much more slowly than insulin. Aldosterone stimulates the production of Na+ -K+ -ATPase, which results in increased enzyme activity and the transport of potassium from the intracellular to extracellular space. In addition, as will be discussed below, aldosterone also regulates renal potassium transport. Thus hyperaldosteronism causes hypokalemia as a result of the combined effects of redistribution and stimulation of renal potassium clearance.

The final major hormonal cause of potassium redistribution includes sympathomimetic agents, beta2 -adrenergic agonists, dopamine, dobutamine, and theophylline. The first three agents directly stimulate the cellular uptake of potassium and also stimulate insulin release, whereas theophylline indirectly stimulates potassium uptake. Sympathomimetic-induced redistribution leading to hypokalemia is important in acute myocardial ischemia and acute asthma therapy. Myocardial ischemia commonly increases sympathetic tone, whether as a direct result of the ischemia, decreased cardiac output, or from either the pain or the anxiety related to the ischemia. Cellular potassium redistribution leading to hypokalemia can then increase the risk of ventricular arrhythmia and sudden death. Treatment of the asthma patient with beta-adrenergic agonists or theophylline can lead to potassium redistribution, hypokalemia, and impairment of respiratory muscle contractile ability. Patients may develop CO2 retention, or, even more seriously, decreased wheezing, as a result of decreased air movement, which might be misinterpreted as an overall improvement in the patient’s condition. Another clinical concern is premature labor therapy involving beta-agonists. These patients frequently do not have oral intake for prolonged periods, providing a setting for the development of severe hypokalemia.

Hypokalemia as a result of potassium redistribution can also occur from acute anabolic states. Cells contain approximately 130 mEq/liter of potassium; consequently, stimulation of either cell hypertrophy or cell production can cause rapid movement of potassium from the extra- to the intracellular space. Rapid cell production can occur in acute leukemia and high-grade lymphomas. Acute stimulation of cell production can result from granulocyte macrophage colony-stimulating factor treatment of refractory anemia or the initial treatment of pernicious anemia with vitamin B12. The resultant cell production can cause acute hypokalemia and in some individuals has resulted in arrhythmias and sudden death.

Rarely, hypokalemia secondary to redistribution with enhanced cellular uptake can be a result of hypokalemic periodic paralysis. Both familial and sporadic cases have been reported. Most hereditary cases follow an autosomal dominant distribution, although an X-linked recessive form has been documented. In Asians there is a high frequency of this condition associated with thyrotoxicosis. Attacks frequently commence during the night or the early morning and are characterized by flaccid paralysis of all extremities, which may persist from 6 to 24 h. A genetic defect in a dihydropyridine-sensitive calcium channel has been determined to cause certain cases of this disorder. Carbonic anhydrase inhibitors (acetazolamide 250 mg four times daily), beta blockers, or spironolactone may prevent attacks.

Finally, hypokalemia has been reported in connection with chloroquine and barium intoxication. The latter effect can be explained by the known action of barium to block potassium channels and, hence, cellular potassium exit.

Non Renal Loss

Both the skin and the gastrointestinal tract can transport significant amounts of potassium. Under normal conditions, net fluid loss from these organs is small, limiting net potassium loss. Occasionally, in cases such as prolonged exertion in hot, dry environments or chronic diarrhea, severe potassium loss can occur, leading to hypokalemia. In most of these cases, intravascular volume depletion is present also, leading to secondary hyperaldosteronism, stimulation of renal potassium excretion, and further worsening of the potassium deficit.

Prolonged loss of gastric contents, whether from vomiting or nasogastric suctioning, can lead to hypokalemia. A small part of this potassium loss is direct because these body fluids contain 5 to 8 mEq/liter potassium. More importantly, concomitant alkalosis and intravascular volume depletion contribute to renal potassium loss. Metabolic alkalosis results in bicarbonaturia, which increases potassium excretion both directly, as a cation to balance the negative charge of bicarbonate ions, and indirectly, through stimulation of urinary sodium excretion, leading to worsening of intravascular volume depletion and stimulation of the renin-angiotensin-aldosterone system. In addition, potassium reabsorption by the collecting duct is affected by acid-base status. Thus metabolic alkalosis increases renal potassium excretion by increasing potassium secretion and probably by direct suppression of potassium reabsorption.

Diarrhea, whether secretory or as a result of laxative abuse, can cause profound gastrointestinal potassium loss. Patients with laxative abuse may deny the condition because of over-concern about body image and may also abuse diuretics. If magnesium- or phosphate-containing cathartics, such as magnesium citrate or sodium phosphate, are suspected, direct measurement of these compounds in the stool can confirm the diagnosis.

Gastrointestinal Loss

  • Diarrhea
  • Laxative Abuse
  • Prolonged Gastric Suction
  • Protracted Vomiting
  • Villose adenoma

Renal Loss

Causes of renal potassium loss

Drugs

Many medications can cause renal potassium wasting, including diuretics and some antibiotics. Both thiazide and loop diuretics increase urinary potassium excretion; when factored for their natriuretic (Sodium wasting) effect, thiazide diuretics are more potent kaliuretic (Potassium wasting) agents. In part this is because loop diuretics have a shorter pharmacologic half-life, enabling renal potassium conservation during periods between drug administration, but may also reflect their site of action in the distal convoluted tubule with secondary effects on flow to the primary site of potassium secretion in the CCD. All diuretics, except the potassium-sparing diuretics, induce potassium-wasting by increasing CCD luminal flow rate, luminal sodium delivery, and luminal electronegativity, which are the primary determinants of potassium secretion by the CCD. They may also induce intravascular volume contraction, resulting in secondary hyperaldosteronism and further stimulation of renal potassium secretion. The incidence of diuretic-induced hypokalemia is both dose- and treatment duration-related.

Antibiotics can increase urinary potassium excretion by a variety of mechanisms. High-dose penicillin and some penicillin analogues, such as carbenicillin, oxacillin, and ampicillin, increase distal tubular delivery of a non-reabsorbable anion, thereby increasing urinary potassium excretion. Cisplatin is another drug that may induce hypokalemia via an increase in renal potassium excretion. Polyene antibiotics, such as amphotericin B, create cation channels in the apical membrane of collecting duct cells, which increases potassium secretion and results in potassium wasting.

Diuretics

  • Thiazide Diuretics
  • Loop Diuretics
  • Osmotic Diuretics

Antibiotics

  • Penicillin and Penicillin analogues
  • Amphotericin B
  • Aminoglycosides**

Hormones

Endogenous hormones are very important causes of hypokalemia. Aldosterone is perhaps the most important hormone regulating total body potassium homeostasis, and excess aldosterone production or effect frequently leads to hypokalemia. The CCD is the primary site in the kidney where aldosterone regulates potassium transport, and the CCD principal cell is the CCD cell responsible for potassium secretion. Aldosterone increases principal cell apical sodium conductance, basolateral Na+ -K+ -ATPase activity, and electrogenic sodium absorption in the CCD. These effects increase the net luminal-negative charge or transepithelial voltage, which increases the electrochemical gradient for potassium movement from the principal cell cytoplasm to the luminal fluid. Thus aldosterone, via actions on apical Na+ channels and basolateral Na+ -K+ -ATPase, increases CCD principal cell potassium secretion. Although potassium reabsorption can occur in the OMCD and IMCD, the reabsorptive capacity of these segments, particularly with normal Na intake, is less than the rate of potassium secretion by the CCD. Thus the net effect of aldosterone is to enhance renal potassium clearance.

Hyperaldosteronism can be either primary or secondary. Primary hyperaldosteronism results in cases of hypertension, predominantly because of the sodium-retaining effects of aldosterone, but the associated hypokalemia may also contribute by sensitizing the vasculature to neurohumoral regulators of blood pressure. Because angiotensin II regulates adrenal gland aldosterone synthesis, conditions involving elevated angiotensin II levels will typically involve hyperaldosteronism. This may occur in a variety of conditions, such as decreased oral intake, diuretic use, vomiting, or diarrhea. Activation of the renin-angiotensin-aldosterone system, as may occur in malignant hypertension, renovascular hypertension, and renin-secreting tumors, can also lead to secondary hyperaldosteronism with subsequent hypokalemia. The secondary activation of the renin-angiotensin-aldosterone system suggests that potassium redistribution significantly contributes to the hypokalemia.

Rarely, genomic defects lead to excessive aldosterone production. In glucocorticoid-remediable aldosteronism, an adrenocorticotropin (ACTH)-regulated gene is linked to the coding sequence of the aldosterone synthase gene, the rate-limiting enzyme for aldosterone synthesis. Aldosterone synthase is no longer regulated by the renin-angiotensin system, and excessive aldosterone production ensures. In congenital adrenal hyperplasia, there is the congenital absence of either 11beta-hydroxylase or 17alpha-hydroxylase, resulting in excess hypothalamic corticotropin-releasing hormone (CRH) secretion and persistent adrenal synthesis of 11-deoxycorticosterone, a potent mineralocorticoid. This condition can be recognized by the associated effects on sex steroid production. 11beta-hydroxylase deficiency results in increased androgen production, leading to early virilization of men and women. In contrast, 17alpha-hydroxylase deficiency inhibits sex hormone metabolism, leading to incomplete development of sexual characteristics.

Under rare conditions, glucocorticoids function as mineralocorticoids, causing hypokalemia and hypertension. Glucocorticoids, such as cortisol, have a high affinity for the mineralocorticoid receptor but are normally prevented from binding to it because the enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSDH) converts cortisol to cortisone, which does not bind to the mineralocorticoid receptor. Some drugs, such as glycerrhetinic acid (found in carbenoxolone, chewing tobacco, and licorice), inhibit 11beta-HSDH, allowing cortisol to exert mineralocorticoid-like effects in the distal nephron. Infrequently, circulating cortisol can exceed the metabolic capacity of 11beta-HSDH and cause hypokalemia. This can occur either in severe cases of Cushing’s disease or in the ectopic ACTH syndrome.

Magnesium depletion

Concomitant magnesium deficiency may prevent correction of hypokalemia. This is particularly true with diuretic-induced hypokalemia and in certain cases of aminoglycoside- and cisplatin-induced potassium wasting, hypokalemia associated with lysozymuria in acute leukemia, and in individuals with Gitelman’s syndrome (see below). Supplementation with oral magnesium supplements, may serve to correct both the magnesium and potassium deficiency.

Intrinsic renal defects

Intrinsic renal defects leading to hypokalemia are rare but have led to important advances in our understanding of renal solute transport. In 1962, Bartter described the association of hypokalemia, hypomagnesemia, hyperreninemia, and metabolic alkalosis. Recent studies show that these patients can be divided into two groups now known as either Bartter’s syndrome or Gitelman’s syndrome. Patients with Bartter’s syndrome are hypercalciuric and present at an early age with severe volume depletion. This condition appears to be a result of defects in either the renal Na-K-2Cl cotransporter gene, NKCC2, or the ATP-sensitive potassium channel, ROMK, both of which are necessary for loop of Henle sodium reabsorption. Gitelman’s syndrome features hypocalciuria, hypomagnesemia, and milder clinical manifestations and presents at a later age. This syndrome appears to be a result of mutations in the thiazide-sensitive NaCl cotransporter. Both Bartter’s syndrome and Gitelman’s syndrome are associated with hypotension and intravascular volume depletion due to renal sodium-wasting. In contrast, Liddle’s syndrome is associated with hypertension, hypokalemia, metabolic alkalosis, and suppressed renin and aldosterone levels. This condition appears to be a result of defects in the CCD principal cell apical sodium channel, ENaC, leading to an increased open probability, excessive sodium reabsorption, and subsequent volume expansion, hypertension, and suppression of renin and aldosterone. Renal potassium wasting occurs because increased CCD sodium reabsorption leads to increased luminal electronegativity and an increased electrochemical gradient for potassium secretion.

Bicarbonaturia

The last major cause of renal potassium wasting is bicarbonaturia. Bicarbonaturia can result from either metabolic alkalosis, distal renal tubular acidosis, or treatment of proximal renal tubular acidosis. In each case, distal tubular bicarbonate delivery increases potassium secretion. Certain cases of distal renal tubular acidosis may reflect primary defects in potassium reabsorption.

Other less common causes

  • Cisplatin
  • Carbonic anhydrase inhibitors
  • Toluene*
  • Leukemia
  • Diuretic phase of acute tubular necrosis
  • Intrinsic renal transport defects
  • Bartter’s syndrome
  • Gitelman’s syndrome
  • Liddle’s syndrome
  • European Licorice Abuse

*Toluene exposure, which can result from sniffing certain glues, can also cause hypokalemia, presumably by renal potassium wasting.

**Aminoglycosides can cause hypokalemia either in the presence or absence of overt nephrotoxicity. The mechanism is not completely understood but may relate to stimulation of magnesium depletion or direct inhibition of potassium reabsorption. However, most antibiotics do not cause hypokalemia, and some, such as trimethoprim and pentamidine, can cause hyperkalemia by inhibition of apical sodium channels in the CCD.

Correction

The risks associated with hypokalemia must be balanced against the risks of therapy when the appropriate approach to the patient is determined. Usually, the primary short-term risks are cardiovascular, and the most important is the proarrhythmogenic effect of hypokalemia. In contrast, the primary risk of overaggressive replacement is the development of hyperkalemia with resultant ventricular fibrillation. Occasionally, incorrect therapy of hypokalemia can lead to paradoxical worsening of the hypokalemia.

Conditions requiring emergent therapy are rare. The classic causes include severe hypokalemia in a patient preparing to undergo emergent surgery, particularly in patients with known coronary artery disease or on digitalis treatment, and the patient with an acute myocardial infarction and significant ventricular ectopy. In such cases, administration of 5 to 10 mEq of KCl over 15 to 20 min may be used to increase serum potassium to a level above 3.0 mEq/liter. This dose can be repeated as needed. Close, continuous monitoring of the serum level and the electrocardiogram (ECG) are necessary to reduce the risk of hyperkalemia.

In most other conditions, the choice of parenteral versus oral therapy is dependent on the ability of the patient to take oral medication and the ability of the GI tract to function appropriately. In many cases, such as myocardial infarction, paralysis, and hepatic encephalopathy, the patient may be unable to take oral potassium safely or questions may exist about the speed of GI tract absorption. In these cases, KCl can be given intravenously. When given via the intravenous (IV) route, replacement can be given safely at a rate of 10 mEq KCl per hour. One study has found that 20 mEq KCl per hour causes the serum potassium level to increase by an average of 0.25 mEq/L per hour. If more rapid replacement is necessary, then 40 mEq per hour can be administered through a central catheter with continuous ECG monitoring. However, replacement therapy should be administered orally if possible.

The parenteral fluids used for potassium administration can affect the response. In nondiabetic patients, IV dextrose increases serum insulin levels, which can cause redistribution of potassium from the extra- to the intracellular space. As a result, providing KCl in glucose solutions such as D5 W can paradoxically lower serum potassium levels. In most cases, parenteral KCl should be provided in normal saline. If large concentrations of KCl are added to the parenteral fluid, then KCl might be administered in half normal saline to avoid administration of a hypertonic solution.

Usually hypokalemia can be treated successfully with oral therapy. Patients with diuretic-induced hypokalemia should be re-evaluated to reconsider the need for diuretics. If continual use is required, assessment of sodium intake should be preformed. Excessive sodium intake accentuates diuretic-induced hypokalemia. If this is not the case concomitant use of the potassium-sparing diuretics amiloride, triamterene, and spironolactone may be considered. When oral replacement therapy is required, KCl is the preferred drug in all patients except those with metabolic acidosis. In the latter condition, either potassium bicarbonate or potassium citrate should be used. The chloride salt of potassium minimizes renal potassium losses. If indicated for other reasons, beta blockers or angiotensin-converting enzyme inhibitors can assist in maintaining potassium levels.

Finally, hypomagnesemia can lead to renal potassium wasting and refractoriness to potassium replacement. In these patients, correction of the hypokalemia does not occur until the hypomagnesemia is corrected. Patients with diuretic-induced hypokalemia, unexplained hypokalemia, or diuretic-induced hypokalemia should have their serum magnesium levels checked and magnesium replacement therapy begun if indicated.

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