Water and electrolyte metabolism

The human body is predominantly composed of water and contains a diverse array of electrolytes. The optimal functioning of the body and its individual cells relies heavily on maintaining adequate levels and balanced ratios of these essential components. To achieve this balance, the body utilizes a complex regulatory system that manages water and electrolyte levels.

Water and electrolytes vary in composition across different fluid compartments within the body. Electrolytes, present as ions, are the primary osmotically active agents influencing the body’s hydration status. The kidneys play a crucial role in regulating this balance, ensuring that water and electrolytes are maintained within their appropriate ranges. Disruption of this regulatory system can lead to complications such as dehydration, hyperhydration, or life-threatening shifts in electrolyte levels.

Compartments

The body's fluid is distributed between two main compartments: the intracellular and extracellular spaces. The intracellular space (ICS), the fluid within the cells, is the largest compartment. The extracellular space (ECS) includes transcellular, intravascular, and interstitial fluid. The volume of distribution for these compartments can be calculated using specific indicator substances.

A common clinical approximation is the "60-40-20 rule": Total body water (TBW) is about 60% of body weight, intracellular fluid (ICF) is about 40% of body weight (or ⅔ of TBW), and extracellular fluid (ECF) is about 20% of body weight (or ⅓ of TBW).

Human water balance is primarily regulated by the osmolarity of the extracellular fluid. Normal osmolarity is 290–295 mosmol/L and is constantly monitored by osmoreceptors in the hypothalamus.

Water content of different tissues

Water content as a percentage of body weight

In older age, there is a reduction in intracellular body water, mainly as a result of muscle mass loss!

Women have a lower water content as a percentage of body weight due to their naturally higher proportion of adipose tissue!

Calculation of volumes of distribution

• Procedure: A known amount of an indicator substance is injected intravenously. After it has equilibrated (e.g., after ∼ 2 h), the concentration of the indicator substance in the plasma is determined. The distribution of the substance in the fluid compartments allows for calculation of the volume of distribution (V).
• Indicators: substances that accumulate only in specific compartments, thus making the content of that compartment indirectly measurable
  • Evans blue: distribution corresponds to the intravascular volume of distribution
  • Inulin: distribution corresponds to the volume of distribution in the extracellular space
  • Antipyrine, deuterium, tritium: distributions correspond to the total body water content
  • Derived value: The intracellular volume of distribution can be calculated from the difference between the volumes of distribution of antipyrine, deuterium, or tritium and inulin
• Calculation: volume of distribution (V) = amount_administered/concentration_plasma

Water is essential for life. It is required for numerous reactions and mechanisms in our body and is used, among other things, as a solvent, coolant, heat buffer, and transport medium.

Water balance

A balanced water state is maintained by matching daily water intake with water excretion, which keeps the body's water content constant.

• Intake (approx. 2.6 L/day; highly variable)
  • From beverages: 1.4 L
  • From food: 900 mL
  • Water of oxidation: 300 mL
• Excretion (approx. 2.6 L/day; highly variable)
  • Via urine: 1.5 L
  • Via respiration and skin: around 900 mL
  • Via stool: 200 mL

Regulation of water balance

The body’s water status is monitored by specialized receptors known as pressoreceptors, volume receptors, and osmoreceptors. Regulation occurs through the sensation of thirst and the kidneys' excretion of water. Various hormones are vital to this process; they are released in response to signals from the receptors and significantly influence water excretion and reabsorption in the kidneys.

Osmoreceptors

The osmolarity of the extracellular fluid is detected by osmoreceptors in the portal venous system and the hypothalamus.

• Water deficit → plasmatic hyperosmolarity → ADH secretion and increased thirst
• Water excess → plasmatic hypoosmolarity → ADH secretion and decreased thirst

Regulation of thirst

The sensation of thirst arises from a water loss of about 0.5% of body weight. Depending on whether the intracellular fluid content decreases or there is a volume deficit in the extracellular space , a distinction is made between osmotic and hypovolemic thirst.

• Osmotic thirst: intracellular osmolality increases → thirst center in the hypothalamus is activated via osmoreceptors → sensation of thirst and ADH secretion increase → increased drinking and increased water retention in the kidney → osmolality decreases
• Hypovolemic thirst: blood pressure and blood volume decrease → pressoreceptors and volume receptors are less activated → increased ADH secretion and activation of the RAAS → increased drinking and increasing water retention in the kidney → blood pressure and blood volume increase

Atrial natriuretic peptide (ANP)

• Function: lowering of blood pressure and blood volume
• Synthesis: in the myocytes of the atria, especially the right atrium
• Stimulation by:
  • Volume increase (increased central venous pressure): registered by stretch sensors in the atria
• Effect: ANP causes a reduction in arterial blood pressure as well as increased natriuresis and diuresis through the following mechanisms, among others:
  • Relaxation of vascular smooth muscle , thereby
    • Decrease in blood pressure
    • Increase in renal medullary blood flow and glomerular filtration rate → enhanced natriuresis and diuresis
  • Inhibition of the epithelial Na⁺ channel in the collecting duct → decrease in renal Na⁺ reabsorption → increase in Na⁺ excretion and consequently also water excretion → lowering of CVP
  • Inhibition of aldosterone, renin, ADH, and ACTH release

Disorders of water balance

Dehydration
Dehydration is a clinical condition that often necessitates treatment, particularly in older adults. Common signs include reduced body weight, low blood pressure, decreased urine output, and elevated hematocrit levels. Treatment for isotonic dehydration involves administering a balanced electrolyte solution. In cases of hypertonic dehydration, such as from intense sweating, more water than electrolytes is lost, resulting in elevated serum sodium levels. This causes water to shift from the intracellular to the extracellular space due to the osmotic gradient, reducing both extracellular and intracellular volumes. However, the amount of hemoglobin remains unchanged, leading to an increase in mean corpuscular hemoglobin concentration (MCHC).

Water for injection
Water for injection is a hypotonic, sterile solution intended solely for preparing, dissolving, or diluting medicinal products. It must never be injected without dissolved drugs, as its hypotonic nature could cause cell and tissue swelling.

Parenteral nutrition
Clinically, electrolyte solutions are used to maintain the body’s mineral levels, while glucose solutions provide parenteral energy. Notably, glucose solutions contain no electrolytes. Glucose requires transporters to enter cells and is metabolized intracellularly. When a 5% glucose solution (D5W) is administered, it initially adds solute to the extracellular fluid (ECF). However, as glucose is rapidly metabolized, it effectively increases free (hypotonic) water, which can raise total body water and risk pulmonary edema, especially if given rapidly or in large volumes.

Osmotic myelinolysis
Rapid correction of hyponatremia through sodium replacement can lead to osmotic myelinolysis. This occurs when increased intravascular osmolarity causes water to exit the myelin sheaths, leading to their damage, particularly affecting the central pons (i.e., central pontine myelinolysis). To prevent this, sodium replacement must be conducted slowly, with continuous monitoring of serum sodium levels.

Sodium (Na⁺) plays a crucial role in regulating water exchange between intracellular and extracellular spaces. Additionally, the sodium gradient across these compartments is essential for generating action potentials and acts as a driving force for secondary active transport processes. In humans, sodium is mainly obtained through dietary intake.

For shifts in sodium balance, see: "Hyponatremia" and "Hyponatremia."

Distribution in the body

• Total content: approx. 85–100 g (55–60 mmol/kg BW)
  • Extracellular (serum concentration): approx. 135–145 mmol/L (95%)
    • Hyponatremia = serum concentration < 135 mmol/L
    • Hypernatremia = serum concentration > 145 mmol/L
  • Intracellular: approx. 10–15 mmol/L (5%)
• Maintenance of sodium distribution: via the Na⁺-K⁺-ATPase

Intake and excretion

Sodium, as a component of table salt, is found in almost all foods. Cheese, meat, seafood, and bread have a particularly high sodium content.

• Average table salt intake: approx. 5–15 g/day
• Average Na⁺ excretion: approx. 3 g/day
  • 95% is excreted via the kidney
  • 5% is excreted via sweat and stool

Regulation

The regulation of sodium concentration occurs via the RAAS and ANP.

Function

• Regulation of water exchange between ICS and ECS
• Sodium gradient
  • Prerequisite for the generation of action potentials
  • Driving force for secondary active transport processes

Arterial hypertension
A high daily intake of table salt is associated with an increased risk of essential (primary) hypertension and cardiovascular diseases. The exact mechanisms underlying this relationship are not yet fully understood. There is ongoing debate regarding the potential role of genetic factors, as familial clustering has been noted in cases of salt-sensitive hypertension. Other risk factors for primary arterial hypertension include smoking, advanced age, obesity, and high alcohol consumption.

Sodium imbalances
Pathological serum sodium concentrations primarily arise from alterations in water balance, resulting in either concentration or dilution of sodium levels. Actual sodium losses due to factors such as diuretics, diarrhea, or vomiting are less common, as are sodium overloads from increased intake. Both hyponatremia and hypernatremia can result in a range of neurological symptoms. For instance, muscle stretch reflexes may become hyperactive, and there is an increased risk of epileptic seizures due to a reduced seizure threshold.

Potassium (K⁺) is the most important osmotic cation of the intracellular space. It is significantly involved in the formation of action potentials and also in the regulation of pH.

For shifts in potassium balance, see: "Hypokalemia" and "Hyperkalemia."

Distribution in the body

• Total content: 140 g (40–50 mmol/kg BW)
  • Extracellular (serum concentration): approx. 3.5–5.0 mmol/L (2%)
    • Hypokalemia = serum concentration < 3.5 mmol/L
    • Hyperkalemia = serum concentration > 5.0 mmol/L
  • Intracellular: approx. 140–160 mmol/L (98%)
• Maintenance of potassium distribution: via the Na⁺-K⁺-ATPase

Intake and excretion

Potassium is ingested through food and is found mainly in oranges, bananas, apricots, figs, meat, and potatoes.

• Average intake: 2–6 g/day (50–150 mmol)
• Average excretion: approx. 50–150 mmol/day (matches intake to maintain balance)
  • Approx. 10% is excreted enterally
  • Approx. 90% is excreted renally (regulated by aldosterone)

Regulation

Potassium concentration is regulated by the RAAS. Here, aldosterone promotes K+ secretion, a process linked to its effect on Na+ reabsorption.

Function

• Influence on the resting membrane potential
• Influence on pH value

Cardiac arrhythmias
A serum potassium concentration that is too low (= hypokalemia) or too high (= hyperkalemia) increases the risk of life-threatening cardiac arrhythmias. Hypokalemia can occur, for example, with severe diarrhea, severe vomiting, or uncontrolled, high-dose insulin therapy (temporary shift of potassium intracellularly). Hyperkalemia is caused, for example, by chronic kidney failure, increased potassium release from body cells (trauma, hemolysis), or insulin deficiency. Depending on the severity, the consequences can range from mild heart palpitations or tachycardia to fatal arrhythmias and cardiac arrest.

Calcium (Ca²⁺), with a body content of approx. 1 kg, is the most abundant mineral in the human organism. However, 99% of it is present as calcium phosphate bound in bone.

For shifts in calcium balance, see: "Hypocalcemia" and "Hypercalcemia."

Distribution in the body

• Total content: approx. 1 kg
  • Extracellular (serum concentration): total calcium approx. 2.20–2.65 mmol/L
    • Hypocalcemia = serum concentration of total calcium < 2.20 mmol/L or ionized calcium < 1.15 mmol/L
    • Hypercalcemia = serum concentration of total calcium > 2.65 mmol/L or ionized calcium > 1.35 mmol/L
    • Approx. 1.15–1.35 mmol/L of this is ionized, unbound, and therefore biologically active calcium
    • The remaining calcium is bound and therefore biologically inactive calcium
  • Intracellular: ionized calcium: approx. 0.0001 mmol/L

Intake and excretion

Calcium is ingested through food and is found mainly in milk and dairy products, cheese, and green vegetables. The Ca²⁺ ions enter the cytosol of enterocytes via an ion channel.

• Average intake: 0.8–1.2 g/day
• Average excretion
  • ⅔ of orally ingested calcium is not absorbed but is excreted with the stool
  • 1% of glomerularly filtered calcium is excreted in the urine, while the remaining 99% is reabsorbed in the renal tubular system.

Regulation

The regulation of calcium balance is subject to a complex mechanism and is regulated by parathyroid hormone, calcitriol, and calcitonin. For more details, see Parathyroid glands.

Function

• Component of signal transduction cascades
  • As an intracellular second messenger (see: "Signal transduction")
  • Increase in presynaptic transmitter release at chemical synapses
• Component of muscle contraction via binding to accessory proteins
• Stabilization of the membrane potential
• Function as a coagulation factor (Factor IV)
• Formation of tooth and bone substance as calcium phosphate (= Ca₃(PO₄)₂)

Acidosis/alkalosis
Calcium competes with protons for binding sites on proteins. In acidosis, characterized by a decrease in blood pH and an increase in protons, there is an elevation of free calcium levels. Clinically, hypercalcemia can present with a wide range of symptoms, including cardiac arrhythmias, muscle weakness, constipation, and paresis, or it may remain asymptomatic. Conversely, in alkalosis, such as that seen in respiratory alkalosis due to hyperventilation during a panic attack, blood pH increases and proton levels decrease, resulting in lower free calcium levels. This can lead to clinical manifestations such as tingling paresthesias, tetany, and cardiac arrhythmias, often referred to as hyperventilation tetany.

Phosphate (PO₄⁻), with a body content of approx. 700 g, is the second most abundant mineral in the human organism (after calcium). Together with calcium, 85% of it is present as calcium phosphate bound in bone.

Distribution in the body

• Total content: approx. 700 g
  • Extracellular (serum concentration): approx. 0.84–1.45 mmol/L (1%)
    • Hypophosphatemia = serum concentration < 0.84 mmol/L
    • Hyperphosphatemia = serum concentration > 1.45 mmol/L
  • Intracellular: 14%

Intake and excretion

Phosphate is ingested through food and is found mainly in fish, meat, nuts, seeds, cheese, and chocolate.

• Average intake: 0.7–1.3 g/day
• Average excretion
  • Approx. ⅓ of orally ingested phosphate is not absorbed and is excreted with the stool (i.e., ⅔ is absorbed)
  • Depending on the serum concentration, 5–20% of the glomerularly filtered phosphate is excreted

Regulation

The regulation of phosphate balance is subject to a complex mechanism and is controlled by parathyroid hormone, calcitriol, and calcitonin. For more details, see Parathyroid glands.

Function

• Regulation of energy metabolism (e.g., in glycolysis in the form of adenosine triphosphate = ATP)
• Formation of tooth and bone substance as calcium phosphate (Ca₃(PO₄)₂)
• Regulation of the acid-base balance (phosphate buffer system)
• Regulation of enzyme activities through phosphorylation and dephosphorylation

Hyperphosphatemia
With a permanently elevated serum phosphate concentration of > 2 mmol/L, the body is no longer able to excrete the excess phosphate via the intestine and kidney. Clinically, this leads to hyperfunction of the parathyroid gland due to increased PTH stimulation, increased bone remodeling or breakdown, and the deposition of calcium phosphate crystals in soft tissues. This causes the serum Ca²⁺ level to drop.

Magnesium (Mg²⁺), with a body content of approx. 20 g, is the fourth most abundant cation in the human organism (after sodium, potassium, and calcium), and 65% of it is bound in bone.

Distribution in the body

• Total content: approx. 20 g (approx. 16 mmol/kg BW)
  • Extracellular (serum concentration): approx. 0.73–1.06 mmol/L (1%)
  • Intracellular: approx. 15 mmol/L (34%)

Intake and excretion

Magnesium is ingested through food and is found mainly in seeds, nuts, cocoa, fruits, and vegetables.

• Average intake: 0.3–0.35 g/day
• Average excretion
  • ⅔ of orally ingested magnesium is not absorbed and is excreted with the stool
  • Approx. 3–5% of the filtered magnesium is excreted

Regulation

Magnesium balance is closely linked to the absorptive capacity of the intestine and kidneys.

• Enteral absorption
  • Is increased by calcitriol, parathyroid hormone, and somatotropin
  • Is inhibited by calcitonin and aldosterone
• Renal reabsorption
  • Is increased by calcitriol
  • Is inhibited by calcitonin

Function

• Regulation of signal transduction as a cofactor for enzymes
• Reduction of neuromuscular excitability by
  • Inhibition of acetylcholine release at the motor end plate
  • Inhibition of Ca²⁺ channels at nerve endings and at the sarcoplasmic reticulum
• Formation of tooth and bone substance

Muscle cramps (tetany)
Magnesium acts as a physiological antagonist to calcium, inhibiting its intracellular accumulation. In cases of hypomagnesemia, the redistribution of calcium into the cells can result in hypocalcemia. Both hypocalcemia and the underlying hypomagnesemia contribute to increased excitability of muscle cells, often presenting clinically as muscle cramps.