Updated: Sep 16, 2016

Author: Eleanor Lederer, MD, FASN; Chief Editor: Vecihi Batuman, MD, FASN

Pathophysiology of Hypokalemia
Gastrointestinal absorption of potassium is complete, resulting in daily excess intake of
approximately 1 mEq/kg/day (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.
Potassium excretion is increased by the following factors:

Aldosterone

High sodium delivery to the collecting duct (eg, diuretics)

High urine flow (eg, osmotic diuresis)

High serum potassium levels

Delivery of negatively charged ions to the collecting duct (eg, bicarbonate)

Potassium excretion is decreased by the following factors:

Absolute aldosterone deficiency or resistance to aldosterone effects

Low sodium delivery to the collecting duct

Low urine flow

Low serum potassium levels

Renal failure

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

Renal factors in potassium homeostasis

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, however, obligatory renal losses are 10-15 mEq/day. 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.

Potassium distribution
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.
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

Physiologic mechanisms for sensing extracellular potassium concentration are not well
understood. Adrenal glomerulosa cells and pancreatic beta cells may play a role in potassium
sensing, resulting in alterations in aldosterone and insulin secretion. [3, 4] As the adrenal and
pancreatic hormonal systems play important roles in potassium homeostasis, this would not
be surprising; 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. Potassium ingestion
stimulates the secretion of insulin, which 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, prolonged potassium deprivation leads to a
decrease in muscle cell sodium-pump expression, resulting in decreased muscle uptake of
potassium. [5, 6, 7]
Thus, there appears to be a well-developed system for sensing potassium by the pancreas and
adrenal glands. 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. This
system results in rapid adjustments in immediate potassium disposal and helps to provide
long-term potassium homeostasis.

Pathogenic mechanisms
Hypokalemia can occur via the following pathogenetic mechanisms:

Deficient intake

Increased excretion

A shift from the extracellular to the intracellular space

Although poor intake or an intracellular shift by itself is a distinctly uncommon cause, several
causes often are present simultaneously.
Increased excretion
The most common mechanisms leading to increased renal potassium losses include the
following:

Enhanced sodium delivery to the collecting duct, as with diuretics

Mineralocorticoid excess, as with primary or secondary hyperaldosteronism

Increased urine flow, as with an osmotic diuresis

Gastrointestinal losses, from diarrhea, vomiting, or nasogastric suctioning, also are common
causes of hypokalemia. Vomiting leads to hypokalemia via a complex pathogenesis. Gastric
fluid itself contains little potassium, approximately 10 mEq/L. However, vomiting produces
volume depletion and metabolic alkalosis, which 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.

Extracellular/intracellular shift
Hypokalemia caused by a shift from extracellular to intracellular space 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, as, for
example, with acute insulin therapy for hyperglycemia.

Additional considerations
Regardless of the cause, hypokalemia produces similar signs and symptoms. Because
potassium is overwhelmingly an intracellular cation and a variety of factors can regulate the
actual serum potassium concentration, an individual can incur very substantial potassium
losses without exhibiting frank hypokalemia. For example, diabetic ketoacidosis results in a
significant potassium deficit; however, serum potassium in a patient presenting with diabetic
ketoacidosis is rarely low and frequently is frankly elevated.
Conversely, hypokalemia does not always reflect a true deficit in total body potassium stores.
Acute insulin administration can drive potassium into cells transiently, producing short-lived
hypokalemia but not signifying potassium depletion.

Complications
Cardiovascular complications
Hypokalemia has widespread actions in many organ systems that, over time, may result in
cardiovascular disease. Cardiovascular complications are clinically the most important
harbingers of significant morbidity or mortality from hypokalemia.
Although hypokalemia has been implicated in the development of atrial and ventricular
arrhythmias, ventricular arrhythmias have received the most attention. Even moderate
hypokalemia may inhibit the sodium-potassium pump in myocardial cells, promoting
spontaneous early afterdepolarizations that lead to ventricular tachycardia/fibrillation. [8]
Increased susceptibility to cardiac arrhythmias is observed with hypokalemia in the following
settings:

Congestive heart failure

Underlying ischemic heart disease/acute myocardial ischemia

Aggressive therapy for hyperglycemia, such as with diabetic ketoacidosis

Digitalis therapy

Treatment with class III antiarrhythmic drugs (eg, dofetilide) [8]

Methadone therapy [9]

Conn syndrome [10]

Low potassium intake has been implicated as a risk factor for the development of
hypertension and/or hypertensive end-organ damage. Hypokalemia leads to altered vascular
reactivity, likely from the effects of potassium depletion on the expression of adrenergic
receptors, angiotensin receptors, and mediators of vascular relaxation. The result is enhanced
vasoconstriction and impaired relaxation, which may play a role in the development of
diverse clinical sequelae, such as ischemic central nervous system events or rhabdomyolysis.
Treatment of hypertension with diuretics without due attention to potassium homeostasis
exacerbates the development of end-organ damage by fueling the metabolic abnormalities.
These patients are then at higher risk for lethal hypokalemia under stress conditions such as
myocardial infarction, septic shock, or diabetic ketoacidosis.
Muscular complications
Muscle weakness, depression of the deep-tendon reflexes, and even flaccid paralysis can
complicate hypokalemia. Rhabdomyolysis can be provoked, especially with vigorous
exercise. However, rhabdomyolysis has also been seen as a complication of severe
hypokalemia, complicating primary hyperaldosteronism in the absence of exercise. [11]
Renal complications
Abnormalities of renal function often accompany acute or chronic hypokalemia. These may
include nephrogenic diabetes insipidus. They also may include metabolic alkalosis from
impaired bicarbonate excretion and enhanced ammoniagenesis, as well as cystic degeneration
and interstitial scarring.
Gastrointestinal complications
Hypokalemia decreases gut motility, which can lead to or exacerbate an ileus. Hypokalemia
also is a contributory factor in the development of hepatic encephalopathy in the setting of
cirrhosis.
Metabolic complications
Hypokalemia has a dual effect on glucose regulation by decreasing insulin release and
peripheral insulin sensitivity. Clinical evidence suggests that the hypokalemic effect of
thiazide is the causative factor in thiazide-associated diabetes mellitus. [12]