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, Alieh Behjat, M.D.[3]

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 normal ratio of intracellular to extracellular potassium in the body is vital for the generation of action potential and results in appropriate cardiac and neuromuscular cells performance. By decreasing the potassium concentration in extracellular space, the amount of the potassium gradient across the cell membrane is risen and results in hyperpolarization. This alteration moves the resting membrane potential from the threshold to a higher level; hence, a bigger than standard stimulus is necessary to generate an action potential. Consequently, reduced excitability in the neurons and muscle cells would appear and cause flaccid muscle paralysis, rhabdomyolysis (in severe hypokalemia), and paralytic ileus.

Pathophysiology of Hypokalemic Heart Arrhythmias

• Hypokalemia in neurons and muscle cells reduces the membrane responsiveness and causes hyperpolarization. But in cardiac cells, specifically in the conducting system, depolarization is observed. The main reason is the alteration of ion selectivity of TWIK-1 K+ channels, which in standard situation leak potassium. During pathological hypokalemia, these channels transport sodium inward the cells, leading to paradoxical depolarization and may result in cardiac arrhythmias.

• Decreased extracellular potassium also suppresses the activity of some potassium channels conductance, and in turn, it delays ventricular repolarization. Prolonged repolarization could also predispose re-entrant arrhythmias.

• Moreover, Hypokalemia can inhibit Na+-K+ ATPase activity, leading to intracellular Na+ And Ca2+ increase. The accumulation of intracellular ca2+ activates calmodulin kinase and, in turn, induces late Na+ and Ca2+ currents and causes a further reduction in repolarization reserve. This would result in early after-depolarization (EAD)–mediated arrhythmias.

Pathophysiology of Hypokalemic in GI system:

• A low level of potassium causes dysfunctional gastrointestinal smooth muscle performance, the slow movement of the GI system, constipation, and paralytic ileus. The primary rationale behind them is the impairment of normal action potential in the muscle cell membrane, which disturbs favorable contraction and cellular depolarization.

References

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