Diagnosis & Complications
A serum [K] below 3.5 mEq/L defines hypokalemia, and Table 4–1 lists some of the causes and clinical conditions associated with this disorder. The most common causes of hypokalemia are the use of thiazide or loop diuretics, vomiting/nasogastric suction, and diarrhea (or laxatives). These etiologies are usually readily apparent unless the patient is covertly using drugs or vomiting. A more elaborate evaluation is necessary when these frequent causes are excluded. It is then important to determine whether hypokalemia is primarily due to an intracellular shift of K or to excessive K renal or gastrointestinal losses (sometimes combined with reduced intake).
Table 4–1. Hypokalemia. ||Download (.pdf)
Table 4–1. Hypokalemia.
Vomiting, nasogastric suction
Osmotic diuresis (uncontrolled diabetes and others)
Excretion of nonreabsorbable anions
Fludrocortisone and others
Licorice (see text)
Tubular toxicity (aminoglycosides, cisplatinum, and others)
Renal tubular acidosis type I and type II (when treated with NaHCO3
Bartter and Gitelman syndrome
Ureteral diversion into colon
Rapid expansion of cell mass
Hypokalemia due to transcellular K shifts may generate impressive clinical presentations. Examples include several forms of hypokalemic periodic paralysis, the administration of β2-agonists to treat obstructive lung disease or premature labor, theophylline poisoning, and conditions that enhance β-agonist activity such as hyperthyroidism and hypothermia. Insulin also drives K into cells and promotes hypokalemia. Barium poisoning and chloroquine overdose block K exit from cells and cause K accumulation within the ICF and profound hypokalemia. Another cause of K accumulation within cells is a rapid expansion of cell mass that occurs during refeeding after prolonged starvation, with rapidly growing tumors, and when patients with severe pernicious anemia are treated with vitamin B12
Patients with hypokalemic periodic paralysis often have a dramatic clinical presentation. At least two distinct subtypes of this syndrome have been characterized: A rare familial form (usually due to an autosomal dominant mutation affecting a calcium channel) and a more common hyperthyroid-associated form. Hyperthyroid periodic paralysis is especially prevalent among young men of Asian (or less often Hispanic) ancestry. They typically present with profound acute muscle paralysis affecting mainly proximal limb muscle groups with sparing of ocular and respiratory muscles. Deep tendon reflexes are generally absent. Paralysis often develops after a period of exercise (which increases β-agonist activity) or following ingestion of carbohydrates (which increases insulin). Clinical signs and symptoms of thyrotoxicosis may be subtle. A prior history of recurrent episodes of weaknesses is common. Plasma [K] is usually below 2 mEq/L, and both hypophosphatemia and mild hypomagnesemia may be seen. Acute treatment with exogenous K salts is appropriate, but rebound hyperkalemia often develops since total body K is normal. Treatment with β-blockers such as propranolol is helpful and correction of the hyperthyroid state is usually curative. The pathophysiology of this disorder is thought to include the effect of thyroid hormone on the Na-K-ATPase, an exaggerated insulin response, the hypera drenergic state of hyperthyroidism, genetic and racial predisposition, and probably inherited mutations of muscle ion transport that remain subclinical until magnified by the hyperthyroid state.
A reduction of total body K stores may be due to gastrointestinal loss, renal loss, or both. The 24-hour urine potassium excretion helps define the etiology. A patient with hypokalemia should excrete less than 20–30 mEq K per day. If this is found, renal losses are generally excluded and either gastrointestinal losses or a transcellular shift should be considered. Higher excretion rates indicate renal K wasting. However, one caveat is that some renal K losses occur intermittently, with intervening periods of appropriate K conservation. For example, diuretics cause excess renal K losses but urine K excretion falls to an appropriately low range when the diuretic effect wears off. Similarly, vomiting or nasogastric suction causes excess renal K loss during the active phase, but K excretion becomes very low in the “equilibrium phase.”
If a 24-hour urine collection cannot be accomplished, an alternative useful measurement is the transtubular [K] gradient, or TTKG. This calculation attempts to correct the urinary [K] for the increase generated by distal water reabsorption after the tubular fluid has exited the CCD. In theory, the TTKG approximates the [K] gradient in the cortical collecting tubule, and is calculated as
A TTKG below 2–3 indicates appropriate renal K conservation in a patient with hypokalemia. However, the TTKG becomes uninterpretable if urine osmolality is less than plasma osmolality or if distal nephron sodium delivery is very low, ie, urine sodium below 20 mEq/L.
Assessment of a patient's volume status and blood pressure provides additional diagnostic clues. Patients with hypokalemia, volume expansion, and hypertension may have primary or exogenous hypermineralocorticoidism. An increased plasma aldosterone level (normal 5–20 ng/dL) and a simultaneous suppressed plasma renin activity (PRA; normal 1–3 ng/mL per hour) indicate autonomous aldosterone secretion. Some advocate calculating an aldosterone/PRA ratio. A ratio greater than 30 and an elevated aldosterone level (above 20 ng/dL) also suggest primary hyperaldosteronism. Autonomous hyperaldosteronism may be due to a unilateral aldosterone-secreting adenoma (Conn syndrome), bilateral adrenal hyperplasia, or rarely, adrenal cancer. Radiologic evaluation often allows determination of the specific syndrome, but adrenal vein sampling is necessary in some cases. Another cause of primary hyperaldosteronism is glucocorticoid-remediable aldosteronism. This rare disorder is due to an autosomal dominant mutation, which leads to sustained synthesis and secretion of aldosterone by ACTH stimulation. Glucocorticoids suppress ACTH and reverse the clinical and biochemical abnormalities of this disorder.
Pseudohyperaldosteronism is characterized by the biochemical and clinical features of an autonomous mineralocorticoid excess state but with suppressed aldosterone levels. It may be due to secretion of a nonaldosterone mineralocorticoid. Examples include adrenal tumors secreting the mineralocorticoid deoxycorticosterone (DOC), some forms of congenital adrenal hyperplasia (17- and 11-hydroxylase deficiency), and conditions that cause glucocorticoids to develop potent mineralocorticoid properties. Glucocorticoids can normally activate the mineralocorticoid receptor. However, the enzyme 11 β-hydroxysteroid dehydrogenase type 2 is present in high concentrations at most sites where mineralocorticoid receptors exist, and inactivates the glucocorticoids. In the absence of this enzyme, physiologic levels of glucocorticoids will produce a mineralocorticoid excess state. The enzyme is congenitally absent or defective in patients with the “apparent mineralocorticoid excess (AME)” syndrome who exhibit a hyperaldosterone-like disorder of hypokalemia, metabolic alkalosis, volume expansion, and hypertension. 11 β-Hydroxysteroid dehydrogenase type 2 is also antagonized by substances such as glycyrrhetinic acid, the active ingredient in true licorice, several decongestants available in Europe, and some brands of chewing tobacco (eg, RedMan). Their excessive use results in the same clinical presentation. Also, this enzyme may be overwhelmed by the markedly elevated cortisol levels in some patients with Cushing syndrome, in particular the form due to ectopic ACTH secretion.
Liddle syndrome also has features of a mineralocorticoid excess state but all known mineralocorticoids are reduced. The disorder is caused by an autosomal dominant mutation, which causes the ENaC in the collecting duct to remain in a persistently open state in the absence of mineralocorticoid stimulation. Clinical and biochemical findings mimic a nonaldosterone mineralocorticoid excess state—volume expansion, hypertension, hypokalemia, metabolic alkalosis, and suppressed levels of renin and aldosterone.
Secondary hyperaldosteronism is a condition characterized by elevated aldosterone levels due to high renin. It occurs in patients with renal artery stenosis, but also in patients with severe hypertension whose major renal arteries are anatomically normal—blood flow in smaller vessels is likely impaired. Rarely, tumors may autonomously secrete renin and thereby cause a state of hyperaldosteronism, hypertension, and hypokalemia. These forms of secondary hyperaldosteronism are all associated with volume expansion and hypertension.
Secondary hyperaldosteronism may also be associated with (and due to) reduced ECF volume and hypotension. This is observed with most diuretics and several renal tubular disorders. Combining high distal renal tubule Na delivery with high aldosterone activity leads to renal K wasting, hypokalemia, and variable degrees of metabolic alkalosis. This is a common effect of loop or thiazide diuretics (acetazolamide will produce hypokalemia and metabolic acidosis due to the excretion of sodium bicarbonate). Combining a loop and thiazide diuretic generates an especially powerful kaliuretic response and the combination should be used judiciously.
Two classes of autosomal recessive genetic disorders mimic the effects of thiazide or loop diuretics. Gitelman syndrome is due to a defect of the thiazide-sensitive NaCl transporter in the early distal renal tubule. Bartter syndrome is caused by one of several generic mutations that impair the function of the Na-K-2Cl transporter in the thick ascending limb of Henle that is inhibited by loop diuretics. Both are characterized by similar clinical and biochemical abnormalities: Volume contraction, hypotension, high levels of urinary prostaglandins, renal K and NaCl wasting, and high renin and aldosterone levels. Distinguishing characteristics are reduced urine calcium excretion and severe hypomagnesemia in Gitelman syndrome patients, but hypercalciuria in those with Bartter syndrome. It is almost impossible to discern these patients from those using diuretics surreptitiously unless urine is assayed for these substances and/or specific genetic mutations are identified. While Bartter syndrome is typically a pediatric disease diagnosed early in life, the phenotype of Gitelman syndrome is often subclinical and is not diagnosed until adulthood.
In the intensive care unit, osmotic diuresis is a relatively common cause of hypokalemia and hypernatremia. It is usually due to hyperglycemia or urea in patients with highly catabolic conditions (acute illness, high-dose steroids) who are also receiving parenteral nutrition or tube feeding. Sodium delivered to the distal tubule together with the glucose or urea is reabsorbed in exchange for K and H. Infusion of mannitol can also generate this syndrome. Several nephrotoxic drugs inappropriately increase distal tubule Na delivery, generating K wasting. Some also cause magnesiuria and hypomagnesemia, which itself promotes kaliuresis. Examples include aminoglycoside antibiotics, amphotericin B, cisplatin, and foscarnet. Patients with acute myeloid or lymphoblastic leukemia may develop proximal or distal tubule dysfunction. Hypokalemia as well as metabolic acidosis, hyponatremia, hypocalcemia, hypophosphatemia, and hypomagnesemia may result.
Na delivered to the distal nephron with a poorly reabsorbed nonchloride anion can accelerate K and H secretion. This is magnified by development of ECF contraction with high levels of renin and aldosterone (Figure 4–2). The disorder occurs in patients treated with high-dose Na-penicillin, during development and treatment of diabetic ketoacidosis (Na-β-hydroxybutyrate), with inhalation of toluene/glue (Na-hippurate), and during vomiting or nasogastric suction (when NaHCO3
spills into the distal tubule and urine). By a similar mechanism, hypokalemia develops when patients with proximal renal tubular acidosis (RTA type 2) are aggressively treated with exogenous bicarbonate salts. Patients with classic distal tubular acidosis (RTA type 1) also have accelerated distal tubule Na-K exchange and hypokalemia. However, in contradistinction to proximal RTA, renal K excretion and hypokalemia improve with NaHCO3 therapy, in part because ECF volume expands.
The colon secretes K and absorbs chloride in exchange for HCO3. When urine comes in contact with the bowel wall, chloride is removed while K and HCO3 are secreted. This results in hypokalemia and a hyperchloremic metabolic acidosis. Clinical situations in which this occurs include ureteral implants into the sigmoid colon and interposition of colon segments between the kidney and bladder.
The best treatment for hypokalemia is prevention. The combination of a loop and thiazide diuretic is particularly kaliuretic and should be used infrequently. Incorporating an aldosterone antagonist (spironolactone or eplerenone) or a distal tubule Na channel blocker (amiloride or triamterene) in the diuretic regimen is helpful. Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) also reduce K losses generated by diuretics, in part by reducing aldosterone levels.
Potassium replacement is necessary when K has been lost and total K stores are reduced. Occasionally, exogenous K is used to treat the acute clinical manifestations generated by severe K shifts into cells. However, such replacement must be done cautiously since total body K stores are normal and rebound hyperkalemia occurs. This has been described following treatment of hypokalemic periodic paralysis, and after cessation of intravenous tocolytic therapy with terbutaline for preterm labor.
Whenever possible, K should be replenished via the oral route. Potassium-rich foods (dried fruit, nuts, bananas, oranges, tomatoes, spinach, potatoes, and meat) are often less effective for replacement because their K content is relatively low compared to total calories and because food K is largely composed of organic salts (see below). K salts are required to replenish major deficits. In general, a plasma [K] between 3 and 3.5 mEq/L represents a K deficit of 200–400 mEq, while a plasma [K] between 2.0 and 3.0 mEq/L requires 400–800 mEq.
Potassium replacement salts are divided into two broad classes: Potassium chloride (KCl) and potassium bicarbonate (KHCO3). Organic K salts can be metabolized, mole for mole, to KHCO3 and are therefore included in the second group. KCl is the most appropriate and effective replacement for K deficits associated with metabolic alkalosis. Conversely, alkalinizing K salts (KHCO3, K-citrate, K-acetate, K-gluconate) are best for hypokalemia associated with metabolic acidosis, such as RTA, or chronic diarrhea. Alkalizing K salts are more palatable and better tolerated than oral KCl. However, organic K salts should not be used to treat hypokalemia associated with metabolic alkalosis. In this setting, alkalinizing K salts are poorly retained and less effectively reverse the K deficit and metabolic alkalosis. Table 4–2 lists the various forms of oral potassium salts.
Table 4–2. Oral Potassium Salts.1 ||Download (.pdf)
Table 4–2. Oral Potassium Salts.1
15 mEq/20 mL
KCl extended release tablets
Micro-K, K-Lor, Slow-K, K-Dur, Kaon-Cl, Klor-Con, Klotrix
Kay Ciel, Klor-Con
20 mEq/15 mL
Kchlor, Kay Ciel, Kaon-Cl
KHCO3 and K-organic salts
KHCO3 effervescent tablets
K-Lyte effervescent tablets, Klor-Con/EF
K citrate liquid
K citrate tablets
K gluconate liquid/tablets
6.7 mEq/5 mL
Kaon Elixir, Glu-K
KHCO3/organic anion mixtures
15 mEq/5 mL
Tri-K, K-Lyte DS
When the oral route cannot be used, or total K deficits are severe, intravenous replacement becomes necessary. A parenteral fluid KCl concentration of 20–40 mEq/L is generally well tolerated. KCl concentrations of 60 mEq/L and greater are painful and may induce peripheral vein necrosis. When intravenous administration of a large volume of fluid is contraindicated, K concentrations of up to 200 mEq/L (20 mEq in 100 mL of isotonic saline) may be given via a central vein, but the administration rate should not exceed 10–20 mEq per hour. Central venous administration of very concentrated K solutions requires a rate-controlling pump. The choice of intravenous fluid must also be considered, because dextrose will increase insulin and shift K into cells, thereby potentially worsening hypokalemia!
Coca SG et al: The cardiovascular implications of hypokalemia. Am J Kidney Dis 2005;45:233-247.
Warnock DG: Hereditary disorders of potassium homeostasis. Best Pract Res Clin Endocrinol Metab 2003;17:505.