eMedicine Specialties > Nephrology > Acid-Base, Fluid, and Electrolyte Disorders

Hypokalemia

Author: Eleanor Lederer, MD, Consulting Staff, Louisville VA Hospital; Professor of Medicine; Interim Chief of Nephrology; Director of Nephrology Training Program; Director, Metabolic Stone Clinic; Director of Outpatient Clinics, Kidney Disease Program, University of Louisville School of Medicine
Coauthor(s): Rosemary Ouseph, MD, Professor of Medicine, Director of Kidney Transplant, University of Louisville School of Medicine; Leslie Ford, MD, Assistant Professor of Medicine, Kidney Disease Program, University of Louisville School of Medicine
Contributor Information and Disclosures

Updated: Aug 5, 2009

Introduction

Background

Potassium homeostasis

Potassium, the most abundant intracellular cation, is essential for the life of the organism. Potassium is obtained through the diet, and common potassium-rich foods include meats, beans, fruits, and potatoes.

Gastrointestinal absorption is complete, resulting in daily excess intake of approximately 1 mEq/kg/d (60-100 mEq). Ninety percent of this excess is excreted through the kidneys, and 10% is excreted through the gut. Potassium homeostasis is maintained predominantly through the regulation of renal excretion. The most important site of regulation is the collecting duct, where aldosterone receptors are present.

Excretion is increased by (1) aldosterone, (2) high sodium delivery to the collecting duct (eg, diuretics), (3) high urine flow (eg, osmotic diuresis), (4) high serum potassium level, and (5) delivery of negatively charged ions to the collecting duct (eg, bicarbonate).

Excretion is decreased by (1) absence or relative deficiency of aldosterone, (2) low sodium delivery to the collecting duct, (3) low urine flow, (4) low serum potassium level, and (5) renal failure.

Kidneys adapt to acute and chronic alterations in potassium intake. When potassium intake is chronically high, potassium excretion likewise is increased. In the absence of potassium intake, obligatory renal losses are 10-15 mEq/d. Thus, chronic losses occur in the absence of any ingested potassium. The kidney maintains a central role in the maintenance of potassium homeostasis, even in the setting of chronic renal failure. Renal adaptive mechanisms allow the kidneys to maintain potassium homeostasis until the glomerular filtration rate drops to less than 15-20 mL/min. Additionally, in the presence of renal failure, the proportion of potassium excreted through the gut increases. The colon is the major site of gut regulation of potassium excretion. Therefore, potassium levels can remain relatively normal under stable conditions, even with advanced renal insufficiency. However, as renal function worsens, the kidneys may not be capable of handling an acute potassium load.

Serum potassium level

Potassium is predominantly an intracellular cation; therefore, serum potassium levels can be a very poor indicator of total body stores. Because potassium moves easily across cell membranes, serum potassium levels reflect movement of potassium between intracellular and extracellular fluid compartments, as well as total body potassium homeostasis.

Mechanisms for sensing extracellular potassium concentration are not well understood. Evidence suggests that adrenal glomerulosa cells and pancreatic beta cells may play a role in potassium sensing, resulting in alterations in aldosterone and insulin secretion.^1,2   As both of these hormonal systems play important roles in potassium homeostasis, these new findings are no surprise; however, the molecular mechanisms by which these potassium channels signal changes in hormone secretion and activity have still not been determined.

Muscle contains the bulk of body potassium, and the notion that muscle could play a prominent role in the regulation of serum potassium concentration through alterations in sodium pump activity has been promoted for a number of years. Insulin stimulated by potassium ingestion increases the activity of the sodium pump in muscle cells, resulting in an increased uptake of potassium. Studies in a model of potassium deprivation demonstrate that acutely, skeletal muscle develops resistance to insulin-stimulated potassium uptake even in the absence of changes in muscle cell sodium pump expression. However, long term potassium deprivation results in a decrease in muscle cell sodium-pump expression, resulting in decreased muscle uptake of potassium.^3,4,5

Thus, there appears to be a well-developed system for sensing potassium by the pancreas and adrenal glands, resulting in rapid adjustments in immediate potassium disposal and for long-term potassium homeostasis. High potassium states stimulate cellular uptake via insulin-mediated stimulation of sodium-pump activity in muscle and stimulate potassium secretion by the kidney via aldosterone-mediated enhancement of distal renal expression of secretory potassium channels (ROMK). Low potassium states result in insulin resistance, impairing potassium uptake into muscle cells, and cause decreased aldosterone release, lessening renal potassium excretion.

Several factors regulate the distribution of potassium between the intracellular and extracellular space, as follows:

• Glycoregulatory hormones: (1) Insulin enhances potassium entry into cells, and (2) glucagon impairs potassium entry into cells.
• Adrenergic stimuli: (1) Beta-adrenergic stimuli enhance potassium entry into cells, and (2) alpha-adrenergic stimuli impair potassium entry into cells.
• pH: (1) Alkalosis enhances potassium entry into cells, and (2) acidosis impairs potassium entry into cells.

An acute increase in osmolality causes potassium to exit from cells. An acute cell/tissue breakdown releases potassium into extracellular space.

Pathophysiology

Hypokalemia can occur due to 1 of 3 pathogenetic mechanisms.

The first is deficient intake. Poor potassium intake alone is an uncommon cause of hypokalemia but occasionally can be seen in very elderly individuals unable to cook for themselves or unable to chew or swallow well. Over time, such individuals can accumulate a significant potassium deficit. Another clinical situation where hypokalemia may occur due to poor intake is in patients receiving total parenteral nutrition (TPN), where potassium supplementation may be inadequate for a prolonged period of time.

The second is increased excretion. Increased excretion of potassium, especially coupled with poor intake, is the most common cause of hypokalemia. The most common mechanisms leading to increased renal potassium losses include enhanced sodium delivery to the collecting duct, as with diuretics; mineralocorticoid excess, as with primary or secondary hyperaldosteronism; or increased urine flow, as with an osmotic diuresis.

Gastrointestinal losses, most commonly from diarrhea, also are common causes of hypokalemia. Vomiting is a common cause of hypokalemia, but the pathogenesis of the hypokalemia is complex. Gastric fluid itself contains little potassium, approximately 10 mEq/L. However, vomiting produces volume depletion and metabolic alkalosis. These 2 processes are accompanied by increased renal potassium excretion. Volume depletion leads to secondary hyperaldosteronism, which, in turn, leads to enhanced cortical collecting tubule secretion of potassium in response to enhanced sodium reabsorption. Metabolic alkalosis also increases collecting tubule potassium secretion due to the decreased availability of hydrogen ions for secretion in response to sodium reabsorption.

The third is due to a shift from extracellular to intracellular space. This pathogenetic mechanism also often accompanies increased excretion, leading to a potentiation of the hypokalemic effect of excessive loss. Intracellular shifts of potassium often are episodic and frequently are self-limited, for example, with acute insulin therapy for hyperglycemia.

Regardless of the cause, hypokalemia produces similar signs and symptoms. Because potassium is overwhelmingly an intracellular cation and because a variety of factors can regulate the actual serum potassium concentration, an individual can incur very substantial potassium losses without exhibiting frank hypokalemia. Conversely, hypokalemia does not always reflect a true deficit in total body potassium stores.

Frequency

United States

In the general population, data are difficult to estimate; however, probably fewer than 1% of people on no medications have a serum potassium level of lower than 3.5 mEq/L. Potassium intake varies according to age, sex, ethnic background, and socioeconomic status. Whether these differences in intake produce different degrees of hypokalemia or different sensitivities to hypokalemic insults is not known. Up to 21% of hospitalized patients have serum potassium levels lower than 3.5 mEq/L, with 5% of patients achieving potassium levels lower than 3 mEq/L. Of elderly patients, 5% demonstrate potassium levels lower than 3 mEq/L.

• In patients on non – potassium-sparing diuretics, hypokalemia is present in 20-50%. African Americans and females are more susceptible. Risk is enhanced by concomitant illness such as heart failure or nephrotic syndrome.
• Other groups with a high incidence of hypokalemia include individuals with eating disorders, published incidence ranging from 4.6%⁶ to 19.7%⁷ in an outpatient setting; patients with AIDS, of which 23.1% of hospitalized patients are hypokalemic; and patients with alcoholism, where the incidence of hypokalemia in the inpatient setting is reportedly as high as 12.6%⁸ and is likely due to a hypomagnesemia-induced decrease in tubular reabsorption of potassium. A relatively new and emerging group of individuals who are at high risk for hypokalemia are patients who have undergone bariatric surgery.⁹

Mortality/Morbidity

• Hypokalemia generally is associated with higher morbidity and mortality, especially due to cardiac arrhythmias or sudden cardiac death. However, an independent contribution of hypokalemia to increased morbidity/mortality has not been conclusively established.
• Patients who develop hypokalemia often have multiple medical problems, making the separation and quantitation of the contribution by hypokalemia, per se, difficult. For further details, see Complications.

Race

• Some suggestion is observed of increased frequency of diuretic-induced hypokalemia in African Americans. The higher frequency of hypokalemia in this group may be due to the lower intake of potassium among African American men (approximately 25 mEq/d) than in their white counterparts (70-100 mEq/d).

Sex

• Some suggestion also is observed of increased frequency of diuretic-induced hypokalemia in women.

Age

• With age, frequency increases, due to increased use of diuretics and poor diet, which often is low in potassium.

Clinical

History

• Symptoms are nonspecific and predominantly are related to muscular or cardiac function.
  • Weakness and fatigue are the most common complaints. The muscular weakness that occurs with hypokalemia can manifest in protean ways, ie, dyspnea, constipation or abdominal distention, or exercise intolerance. Rarely, muscle weakness progresses to frank paralysis.
  • Occasionally, a patient may complain of worsening diabetes control or polyuria due to a recent onset of hyperglycemia or nephrogenic diabetes insipidus.
  • The patient also may complain of palpitations.
  • With severe hypokalemia or total body potassium deficits, muscle cramps and pain can occur with rhabdomyolysis.
• When the diagnosis of hypokalemia is discovered, investigate potential pathophysiologic mechanisms.
  • Poor intake may result from the following:
    • Eating disorders
    • Dental problems
    • Poverty
  • Increased excretion may be due to the following:
    • Medications, including diuretics, AIDS therapy, or antibiotics
    • Polyuria
    • Vomiting or diarrhea
  • Shift of potassium into the intracellular space may occur due to the following:
    • Recurrent episodes of paralysis
    • Use of high doses of insulin
    • High-dose beta agonist therapy (eg, for chronic obstructive pulmonary disease)

Physical

• Vital signs generally are normal, except for occasional tachycardia or tachypnea due to respiratory muscle weakness.
  • Hypertension may be a clue to primary hyperaldosteronism, renal artery stenosis, licorice ingestion, or the more unusual forms of genetically transmitted hypertensive syndromes such as congenital adrenal hyperplasia, glucocorticoid remediable hypertension, or Liddle syndrome.
  • Relative hypotension should suggest occult laxative use, diuretic use, bulimia, or one of the unusual tubular disorders such as Bartter syndrome or Gitelman syndrome (see Bartter Syndrome). Bear in mind that occult diuretic use is far more common than either congenital tubular disorder and is, in fact, also called "pseudo Bartter."
• Muscle weakness and flaccid paralysis may be present.
• Patients may have depressed or absent deep-tendon reflexes.

Causes

Pathophysiologic mechanisms include poor intake, increased excretion, or a shift of potassium from the extracellular to the intracellular space. Mechanisms causing increased excretion are the most common. Singly, poor intake or an intracellular shift is a distinctly uncommon cause. Often, several disorders are present simultaneously.

• Poor intake
  • Eating disorders: Anorexia, bulimia, starvation, pica, and alcoholism
  • Dental problems: Inability to chew or swallow
  • Poverty: Lack of food, ie, "tea-and-toast" diet of elderly individuals
  • Hospitalization: Potassium-poor TPN
• Increased excretion
  • Endogenous mineralocorticoid excess
    • Cushing disease
    • Primary hyperaldosteronism, most commonly due to adenoma or bilateral adrenal hyperplasia
    • Secondary hyperaldosteronism due to volume depletion, congestive heart failure, cirrhosis, or vomiting
    • Adrenocortical carcinoma
    • Tumor that is producing adrenocorticotropic hormone
    • Congenital disorders - Congenital adrenal hyperplasia (11-beta hydroxylase or 17-alpha hydroxylase deficiency) or glucocorticoid-remediable hypertension
  • Hyperreninism due to renal artery stenosis
  • Exogenous mineralocorticoid excess
    • Steroid therapy for immunosuppression
    • Glycyrrhizic  acid -  Inhibits 11-beta hydroxysteroid dehydrogenase; contained in licorice and Chinese herbal preparations
    • Renal tubular disorders - Type I and type II renal tubular acidosis
    • Hypomagnesemia
  • Congenital disorders
    • Bartter syndrome: This is a group of autosomal-recessive disorders characterized by hypokalemic metabolic alkalosis and hypotension. Mutations in 6 different renal tubular proteins in the loop of Henle have been discovered in individuals with clinical Bartter syndrome.^10,11 They are the NaKCl (NKCC2) transporter; the ROMK1 potassium channel; the chloride channel CLCKa either alone or in combination with the chloride channel CLCKb; the calcium sensing receptor; and barttin, a protein required for the surface expression of the chloride channels. The most severe cases present antenatally or neonatally with profound volume depletion and hypokalemia. Less severe cases present in childhood or early adulthood with persistent hypokalemic metabolic alkalosis that is resistant to replacement therapy. Type IV, a variant to the classic Bartter syndrome, is associated with sensorineural hearing loss.
    • Gitelman syndrome: This is an autosomal-recessive disorder characterized by hypokalemic metabolic alkalosis and low blood pressure. It is caused by a defect in the thiazide-sensitive sodium chloride transporter in the distal tubule. Compared to Bartter syndrome, it generally is milder, presents later, and is complicated by hypomagnesemia. In contrast, patients with Bartter syndrome generally do not develop hypomagnesemia. Hypocalciuria is also frequently found in Gitelman syndrome, while the patients with Bartter syndrome are more likely to have increased urinary calcium excretion.
    • Liddle syndrome: This syndrome is an autosomal-recessive disorder characterized by a mutation in the epithelial sodium channel in the aldosterone-sensitive portion of the nephron, leading to unregulated sodium reabsorption, hypokalemic metabolic alkalosis, and severe hypertension.
  • Osmotic diuresis: Mannitol and hyperglycemia can cause osmotic diuresis.
  • Increased gastrointestinal losses: Losses can result from diarrhea or small intestine drainage. The problem can be particularly prominent in tropical illnesses, such as malaria or leptospirosis.¹²  Severe hypokalemia has also been reported with villous adenoma or VIPomas.¹³
  • Drugs
    • Diuretics (carbonic anhydrase inhibitors, loop diuretics, thiazide diuretics): Increased collecting duct permeability or increased gradient for potassium secretion can result in losses.
    • Some penicillins
    • Exogenous bicarbonate ingestion
    • Amphotericin B, azole class of antifungal agents, echinocandin class of antifungal agents¹⁴
    • Gentamicin
    • Cisplatin
    • Stacker 2¹⁵
    • Beta-agonist intoxication¹⁶
• Shift of potassium from extracellular to intracellular space
  • Alkalosis, metabolic or respiratory
  • Insulin administration or glucose administration: This stimulates insulin release.
  • Intensive beta-adrenergic stimulation
  • Hypokalemic periodic paralysis is a rare disorder with recurrent periods of hypokalemic paralysis between periods of normal serum potassium levels. In most cases, it is due to an abnormality in the alpha 1 subunit of the dihydropyridine-sensitive calcium channel in the skeletal muscle. How a defect in a calcium channel produces hypokalemic paralysis is not well understood.
  • Thyrotoxic periodic paralysis is an acquired form of hypokalemic periodic paralysis and is most common in Asian males. The mechanism by which hyperthyroidism produces hypokalemic paralysis is not yet understood, but theories include increased Na-K-ATPase activity, which has been found in patients with both thyrotoxicosis and paralysis. 
  • Refeeding: This is observed in prolonged starvation, eating disorders, and alcoholism.

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