Hypokalemia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor-In-Chief: Cafer Zorkun, M.D., Ph.D. [2], Aida Javanbakht, M.D.Assistant Editor(s)-In-Chief: Jack Khouri

Overview

• Potassium is the most common intracellular cation. Approximately 98% of total potassium exists in the intracellular fluid (ICF), which has a normal range of 140–150 mEq/l. Merely 2% of this cation is placed in the extracellular fluids (ECF), where it ranges from 3.5 to 5 mEq/l. Potassium is essential during numerous body functions, particularly for excitable cells such as muscle and nerve cells. Any disorder of potassium serum levels can disturb the transmembrane potential and renders excitable cells (nerve and muscle) hyperpolarized and less sensitive. However, cardiac cells don't obey this rule and become hyperexcitable. Potassium regulation is essential to maintain a normal activity in cells. Any impairment in potassium serum levels will have severe consequences on several organs especially the heart and the nervous system. Typically, total potassium excretion in the stool is low and most ingested potassium is absorbed. The kidney is the primary regulator of potassium balance through excretion (the kidney excretes 90-95% of dietary potassium); the gut excretes a minimal amount of dietary potassium (approximately 10%).

Pathophysiology

Hypokalemia can result from several conditions:

• Trans-cellular shifts of potassium inside the cells (most common)
• Renal loss of potassium
  • Increased distal Na delivery
  • Increased urine flow
  • Metabolic alkalosis
  • Increased aldosterone level
• Gastrointestinal (GI) loss of potassium
• Increased hematopoiesis (increased cellular use of potassium)
• Decreased intake of potassium (least common)

Shown below is a table summarizing the different pathophysiological processes that can lead to hypokalemia.

Trans-cellular shifts	Renal loss		GI loss	Increased hematopoiesis	Decreased intake of potassium
Metabolic alkalosis (K+/H+ exchanger) Insulin (activates Na+/K+ ATPase) Catecholamine (activates Na+/K+ ATPase) Hypokalemic thyrotoxic periodic paralysis Hypothermia Chloroquine Barium intoxication Cesium intoxication Antipsychotic overdose	Subject is normo or hypotensive Associated with acidosis Diabetic ketoacidosis Renal tubular acidosis type 1 Renal tubular acidosis type 2 Associated with alkalosis Diuretics Vomiting (increase in aldosterone) Bartter's syndrome (dysfunction of in loop of Henle) Gitelman's syndrome (dysfunction in distal convoluted tubules) Variable acid/base status Hypomagnesemia	Subject is hypertensive Primary hyperaldosteronism Conn's syndrome Secondary hyperaldosteronism Renovascular disease Renin secreting tumor Non aldosterone increase in mineralcorticoid Cushing's disease Congenital adrenal hyperplasia Increased mineralcorticoids Licorice ingestion Liddle's syndrome	Associated with metabolic acidosis Diarrhea Laxative abuse Villous adenoma Associated with metabolic alkalosis Vomiting Nasogastric tube drainage	Megaloblastic anemia Treatment of anemia Crisis of AML	Tea and toast diet Anorexia nervosa Alcoholism

The Role of the Kidney

• The Kidneys play a vital role in keeping the balance of potassium.
• At the glomerulus, potassium is freely filtered and reabsorbed mainly in the proximal tubule and thick ascending limb of loop of Henle (>60 % of filtered potassium).
• The cortical collecting duct receives 10–15% of filtered potassium and constitutes the kidney’s primary site of potassium excretion.
• Potassium excretion at the cortical collecting duct depends on the amount of sodium delivered there and the activity of aldosterone.
• The absorption of sodium by the principal cells of the cortical collecting ducts is mediated by the apical epithelial sodium channels (ENaC); when the amount of sodium delivered to the cortical collecting duct is very high, the absorption of sodium increases without concomitant absorption of the accompanying anions (e.g., bicarbonates and chloride ions) which are not easy to absorb. This physiologic process causes the formation of a negative charge within the cortical collecting duct lumen, causing potassium and proton secretion.
• Aldosterone increases sodium absorption at the cortical collecting duct by means of enhancing the activity of Na-K-ATPase pumps and augmenting the number of the ENaC channels.

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Factors Increasing Kidney Potassium Excretion

• Aldosterone
• High urine flow rate
• High distal sodium delivery
• Metabolic alkalosis
• High extracellular fluid K+ concentration

Some Factors Affecting Potassium Distribution Between the Cells and the Extracellular Fluid

• Na/K ATPase
• Insulin
• Catecholamines
• Plasma potassium concentration
• Extracellular pH
• Hyperosmolarity

The Physiologic Role of Potassium

• Potassium is the most common intracellular cation. Approximately 98% of total potassium exists in the intracellular fluid (ICF), which has a normal range of 140–150 mEq/l. Merely 2% of this cation is placed in the extracellular fluids (ECF), where it ranges from 3.5 to 5 mEq/l.
• Potassium is essential during numerous body functions, particularly for excitable cells such as muscle and nerve cells.
• Diet, mostly fruits and vegetables, is the major source of potassium for the body.

The Cellular Effect of Hypokalemia

• The electrochemical gradient of potassium between intracellular and extracellular space is essential for function of neurones; in particular, potassium is needed to repolarize the cell membrane to a resting state after an action potential has passed.
• Decreased potassium levels in the extracellular space will cause hyperpolarization of the resting membrane potential ie, it becomes more negative. This hyperpolarization is caused by the effect of the altered potassium gradient on resting membrane potential as defined by the Goldman equation. As a result, the cell becomes less sensitive to excitation and a greater than normal stimulus is required for depolarization of the membrane in order to initiate an action potential. Clinically, this membrane hyperpolarization results in muscle flaccid paralysis, rhabdomyolysis (in severe hypokalemia) and paralytic ileus.
• At the renal level, hypokalemia can cause metabolic alkalosis due to potassium/proton exchange across the cells and nephrogenic diabetes insipidus.

Pathophysiology of Hypokalemic Heart Arrhythmias

• Potassium is essential to the normal muscular function, in both voluntary (i.e skeletal muscle, e.g. the arms and hands) and involuntary muscle (i.e. smooth muscle in the intestines or cardiac muscle in the heart).
• Severe abnormalities in potassium levels can seriously disrupt cardiac function, even to the point of causing cardiac arrest and death.
• As explained above, hypokalemia makes the resting potential of potassium [E(K)] more negative. In certain conditions, this will make cells less excitable. However, in the heart, it causes myocytes to become hyperexcitable. This is due to two independent effects that may lead to aberrant cardiac conduction and subsequent arrhythmia:
  • There are more inactivated sodium (Na) channels available to fire.
  • The overall potassium permeability of the ventricle is reduced (perhaps by the loss of a direct effect of extracellular potassium on some of the potassium channels), which can delay ventricular repolarization.

Pathophysiology of Hypokalemic in GI system:

• Low level of potassium cause slow movement of GI system and illeus.

References

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