Hypokalemia, or Low Potassium
By Shawna Kopchu R.N.
Hypokalemia refers to a below normal serum potassium concentration. It usually indicates a real deficit in total potassium stores; however, it may occur in patients having normal potassium stores when alkalosis is present (since alkalosis causes a temporary shift of serum potassium into the cells).
Hypokalemia is frequently encountered in clinical medicine and has been estimated to occur in approximately 20% of patients admitted to general internal medicine service. Symptoms may be absent, identified only on routine electrolyte screening, or may range from neuromuscular weakness, rarely progressing to frank paralysis or sudden cardiac death. Usually correction of hypokalemia is not difficult, but if therapy is not appropriate, symptoms may worsen with potentially severe, even lethal, consequences.
Although less than 1% of healthy adults not receiving pharmacologic agents exhibit hypokalemia, the frequency of hypokalemia largely depends on the patient population. The low frequency of hypokalemia is due to both the adequacy of K+ in the typical Western diet and the potent mechanisms for renal K+ conservation in states of K+ depletion. The presence of spontaneous hypokalemia in otherwise healthy adults taking no medicines should suggest the probability of an underlying disease and the need to determine the cause.
Most cases of hypokalemia occur in the setting of specific disease states. Patients receiving thiazide and loop diuretics are at the highest risk, with as many as 50% developing serum K+ levels of less than 3.5 mEq/L. Thiazide diuretics are more likely to cause hypokalemia than loop or osmotic diuretics. Carbonic anhydrase inhibitors, used for refractory glaucoma, produce significant kaliuresis initially, but the ensuing K+ depletion and metabolic acidosis prevent continued K+ loss. Individuals with secondary hyperaldosteronism, whether due to congestive heart failure, hepatic insufficiency, or nephrotic syndrome, may also exhibit hypokalemia. Finally, patients with diseases that alter renal K+ conservation through increased salt delivery are at high risk for hypokalemia.
Consequences of Hypokalemia
Potassium deficiency alters the function of several organs and most prominently affects the cardiovascular system, neurologic system, muscles, and kidneys. These effects ultimately determine the morbidity and mortality related to this condition. Unfortunately, the correlation between degree of potassium deficiency and adverse side-effects is poor, possibly because the occurrence of side-effects is related to both the potassium deficiency and the underlying disease state. Overall, children and young adults tolerate more severe degrees of hypokalemia with less risk of severe side-effects than the elderly.
Two major side-effects of hypokalemia affect the cardiovascular system: hypokalemia-related hypertension and hypokalemia-induced ventricular arrhythmias. Both contribute to increased morbidity and mortality.
Hypokalemia contributes to hypertension in many patients but is frequently unrecognized as an important factor that may produce or worsen this serious health problem. Several lines of evidence reveal that potassium deficiency can increase blood pressure. Cross-sectional studies show that low-potassium diets, especially in the presence of a high sodium intake, are linked with the prevalence of hypertension. This association is most marked in African Americans. Epidemiologic and prospective studies confirm this association in both healthy volunteers and in essential hypertensive patients. The antihypertensive effect of thiazide diuretics is reduced by hypokalemia and enhanced by potassium repletion. Finally, blood pressure may be more highly sodium-dependent in the presence of hypokalemia. Thus evidence strongly indicates that hypokalemia contributes to hypertension.
The mechanism of hypokalemia-induced hypertension is not completely clear. One component of this type of hypertension appears to be salt retention. Hypokalemia leads to intravascular volume expansion as a result of renal NaCl retention. Hypokalemia may also potentiate the hypertensive effects of various neurohumoral agents.
Ventricular arrhythmias are a second cardiovascular side-effect of hypokalemia. Several prospective studies show that hypokalemia predisposes patients to the development of a variety of ventricular arrhythmias, including ventricular fibrillation. Patients at the highest risk for arrhythmias, the elderly and those patients with underlying ischemic heart disease, appear to have the highest risk for hypokalemia-related complications. Diuretic-induced hypokalemia is of particular concern because the incidence of sudden death in hypertensive individuals treated with the thiazide diuretic hydrochlorothiazide is greater than that in matched control subjects. The effect is dose-related and is decreased by the concomitant use of potassium-sparing diuretics.
Hypokalemia impairs both insulin release and end-organ sensitivity to insulin, resulting in worsening hyperglycemia in diabetic patients. Hyperglycemia and diabetes mellitus are major public health concerns in industrialized nations. Because increasing evidence suggests that end-organ complications from diabetes mellitus are related to the degree of hyperglycemia, treatment of hypokalemia may decrease the devastating effects of diabetes mellitus.
Potassium depletion can result in several muscular-related complications. Hypokalemia can hyperpolarize skeletal muscle cells, impairing their ability to develop the depolarization necessary for muscle contraction. It can also reduce blood flow to skeletal muscles. The reduced blood flow can predispose patients to rhabdomyolysis, especially when vigorous exercise is combined with impaired blood-flow regulation. The combination of these effects frequently leads to muscle weakness, easy fatigability, cramping, and myalgias. Paralysis, although uncommon, can occur in cases of profound potassium deficiency.
Hypokalemia can profoundly affect systemic acid-base homeostasis through its effects on multiple components of renal acid-base regulation. The most common abnormality is metabolic alkalosis. Hypokalemic metabolic alkalosis results from the effects of hypokalemia on several components of net acid excretion. The most direct effects include stimulation of proximal tubule HCO3 – reabsorption and ammoniagenesis; collecting duct proton secretion, possibly via stimulation of both the gastric (HKalpha1 ) and colonic (HKalpha2 ) isoforms of H+ -K+ -ATPase; and decreasing urinary citrate excretion. Hypokalemia may produce these widespread effects on renal acid-base homeostasis because of intracellular acidification. Hypokalemia also inhibits aldosterone secretion, which possibly minimizes such effects on acid-base homeostasis. In rare cases, severe hypokalemia leads to respiratory muscle weakness and the development of respiratory acidosis. In patients with hypokalemia as a result of renal tubular acidosis, the concomitant development of respiratory acidosis can be life-threatening.
Another complication of hypokalemia is the development of mild polyuria, averaging 2 to 3 liters per day. The polyuria is related to both increased thirst and mild nephrogenic diabetes insipidus. Increased thirst is associated with increased central nervous system levels of angiotensin II, a hormone that, besides its other effects, regulates thirst. Hypokalemia also impairs the kidney’s ability to concentrate the urine maximally. This appears to occur because hypokalemia causes defective activation of renal adenylate cyclase, preventing antidiuretic hormone-stimulated urinary concentration.
Renal Cystic Disease
Hypokalemia, in association with hyperaldosteronism, can lead to renal cystic disease. These cysts appear to arise in the collecting duct epithelium and are frequently associated with interstitial scarring. Correcting the hypokalemia leads to cyst regression. The mechanism of cyst development is unclear. Hypokalemia leads to increased ammoniagenesis and medullary ammonia accumulation, which may activate the complement system. It has been postulated that hypokalemia, by leading to activation of complement in the medullary interstitium, leads to interstitial fibrosis. Consistent with this hypothesis is the observation that bicarbonate supplementation, by inhibiting ammoniagenesis, decreases the interstitial fibrosis associated with hypokalemia; this effect is independent of changes in serum potassium.
Hypokalemia can contribute to the development, or worsen the symptoms, of hepatic encephalopathy. One toxin that causes hepatic encephalopathy is ammonia, and hypokalemia increases proximal tubule ammoniagenesis. Approximately 50% of proximal tubule ammonia production is returned to the systemic circulation via the renal veins. In hepatic insufficiency, the increased systemic burden of ammonia resulting from increased renal ammoniagenesis can be sufficient to cause the development or worsen the symptoms of hepatic encephalopathy.
Physiology of Potassium Homeostasis
Serum potassium concentration is a balance between intake, excretion, and distribution between the intra- and extracellular space. The average daily potassium intake in a typical Western diet is 70 mEq. Under normal conditions, excretion equals intake, with approximately 90% of potassium excreted in the urine and the vast majority of the remainder in the stool. Distribution of potassium between the intra- and extracellular space plays an important role in potassium homeostasis.
Most potassium is present in the intracellular space. Intracellular potassium averages 120 to 140 mEq/liter, largely as a result of active potassium uptake by Na+ -K+ -ATPase. Approximately 98% of total body potassium is present in the intracellular space. Consequently, small changes in the distribution of potassium between the intra- and extracellular fluid spaces result in proportionally large changes in extracelluar potassium concentration. The large intracellular potassium store functions to minimize changes in extracellular potassium in states of potassium deficiency. Under these conditions, potassium shifts from the intra- to the extracellular fluid, apparently to reduce changes in the transmembrane potassium gradient. With potassium depletion, certain tissues, notably muscle, exhibit a more rapid reduction in intracellular potassium than do others, such as the brain. As a result, small potassium losses minimally affect the serum potassium level. Conversely, the potassium deficit in hypokalemic states that result from potassium loss (excluding pseudohypokalemia and redistribution, as will be discussed below) is very large. For example, a decrease in serum potassium from 3.5 to 3.0 mEq/liter typically indicates a total body potassium deficit of 100 to 300 mEq, and a decrease to 2.0 mEq/liter can indicate a total body deficit of 600 to 800 mEq.
Potassium is present in most foods in varying amounts. Although the typical dietary intake averages 70 mEq/d, there is considerable variation, depending on the dietary preferences of the individual. In the absence of other factors, the body can adapt to a wide range of potassium intake without development of marked hypokalemia. Notably, African Americans commonly eat diets containing less potassium, which may induce a state of physiologic potassium deficiency and contribute to the incidence and severity of hypertension in this population.
The primary mechanism of potassium excretion is the urine. Potassium is freely filtered at the glomerulus, followed by reabsorption of approximately 85% by the proximal tubule and the loop of Henle. Relatively little regulation of potassium reabsorption occurs in these segments, however. Instead, the primary site for renal potassium regulation is the collecting duct. The CCD both secretes and reabsorbs potassium, whereas the outer and inner medullary collecting ducts (OMCD and IMCD, respectively) reabsorb potassium.
At least three cell types are present in the CCD, all of which may contribute to potassium homeostasis. The principal cell is the most numerous cell, comprising 60 to 70% of the CCD, and is believed to be responsible for potassium secretion. Potassium is actively taken up into the cell via a basolateral Na+ -K+ -ATPase and secreted down its electrochemical gradient into the luminal fluid (urine) via an apical potassium channel. Additional evidence indicates that potassium secretion is codependent on Cl secretion. Electrogenic sodium reabsorption generates a lumen-negative charge or voltage. Because this negative charge increases the electrochemical gradient for potassium secretion, the rate of sodium reabsorption also regulates the rate of potassium secretion.
In contrast to the principal cell, the CCD A- and B-type intercalated cells (A cell and B cell, respectively), which comprise the remainder of the CCD, are modeled to reabsorb luminal potassium. Potassium reabsorption occurs through processes different from those of principal cell potassium secretion. An apical H+ -K+ -ATPase secretes protons and reabsorbs luminal potassium, contributing to urinary acidification and potassium reabsorption. In the presence of normal potassium, most reabsorbed potassium is recycled across the apical membrane, resulting in little net potassium transport. In response to potassium deprivation, potassium can exit the cell via a basolateral barium-sensitive transporter, presumably a potassium channel. This provides a sensitive mechanism that allows active potassium reabsorption when necessary.
Recent studies show that the B cell, generally believed to mediate bicarbonate secretion and recovery from metabolic alkalosis, may also contribute to potassium homeostasis. Results from our laboratories and those of others provide strong functional evidence for an apical H+ -K+ -ATPase in this cell. We have also shown that there is coupling of chloride reabsorption by the apical Cl- /HCO3 – exchanger to the apical H+ -K+ -ATPase. Parallel operation of apical H+ -K+ -ATPase and apical Cl- /HCO3 – exchange provide a new model for active KCl reabsorption. Additionally, inhibition of H+ -K+ -ATPase reduces CCD amiloride-insensitive sodium reabsorption, suggesting that sodium can substitute for potassium on the CCD H+ -K+ -ATPase. In hypokalemia, the increased CCD H+ -K+ -ATPase activity, in combination with sodium substituting for potassium on the H+ -K+ -ATPase, could lead to net NaCl reabsorption, volume expansion, and the increased blood pressure that is observed clinically.
The OMCD and IMCD do not transport potassium under normal conditions, but in response to hypokalemia or potassium deficiency can reabsorb potassium. This appears to occur via mechanisms similar to the CCD A cell, e.g., luminal potassium uptake by an apical H+ -K+ -ATPase and basolateral potassium exit via a basolateral potassium channel. As noted previously, at least two isoforms of H+ -K+ -ATPase are present in the collecting duct: HKalpha1 and HKalpha2. HKalpha1 may be regulated to a greater extent by hypokalemia than HKalpha2 in the CCD, whereas the opposite appears to be true in the OMCD.
Despite the presence of active potassium reabsorptive transporters in the CCD, OMCD, and IMCD, the urinary potassium level is generally not lower than 15 to 20 mEq/liter. This may reflect both water reabsorption, which exceeds potassium reabsorption, and persistent potassium secretion in the CCD.
Little potassium is excreted in the stool under normal conditions because of a low stool volume and a low stool potassium concentration. Conditions that increase stool potassium concentration, such as chronic renal failure and hyperkalemia, or stool volume, such as diarrhea, increase fecal potassium excretion. Chronic renal failure can cause adaptive changes in stool potassium content, such that as much as 20 to 30 mEq/d can be excreted by this route. Decreases in stool potassium content do not materially affect the response to hypokalemia because the basal level of stool potassium excretion is normally small.Print This Post
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