Hyponatremia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Saeedeh Kowsarnia M.D.[2]

Overview

The exact pathogenesis of [disease name] is not fully understood.

OR

It is thought that [disease name] is the result of / is mediated by / is produced by / is caused by either [hypothesis 1], [hypothesis 2], or [hypothesis 3]

OR

[Pathogen name] is usually transmitted via the [transmission route] route to the human host.

OR

Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell.

OR

Blo [Disease or malignancy nme] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells].

OR

The progression to [disease name] usually involves the [molecular pathway].

OR

The pathophysiology of [disease/malignancy] depends on the histological subtype.

Pathophysiology

Sodium is the main cation in the extracellular fluid, thus the plasma concentration of sodium is determinant of tonicity and serum osmolality.

The osmotic gradient of solutes that do not cross cell membranes constitutes serum Tonicity which determines the distribution of water in the body.

Plasma tonicity = (Extracellular solute + Intracellular solute) / TBW

Serum or plasma osmolality measures different solutes in plasma. It helps to evaluate the etiology of hyponatremia and screen other solutes in serum.

Serum Osmolality = (2 x (Na + K)) + (BUN (mg/dL) / 2.8) + (glucose (mg/dL) / 18) + (Ethanol (mg/dL) /3.7)

Normal Range= 275–295 mosm /kg (mmol /kg)

Normal range		Osmolality versus Osmolarity
Sodium‡	135-145 mEq/L	Osmolality is a measure of the osmoles (Osm) of solute per kilogram of solvent (osmol/kg or Osm/kg) Osmolarity is described as the number of osmoles of solute per liter (L) of solution (osmol/L or Osm/L) (one liter of plasma equals to one kilogram of plasma,plasma osmolarity and plasma osmolality would be the same)
Potassium‡	3.5-5.1 mEq/L
Blood Urea Nitrogen	7-20 mg/dL (2.5-7.1 mmol/L)
Glucose	70-100 mg/dL ( 3.9-5.5 mmol/L)

‡ Mmol and Meq are the same for univalent ions like sodium, potassium, for Na⁺, Cl^-, Ca²⁺, urea, and glucose, 1 mmol/L equals 1 mOsmol/kg

Plasma water is regulated by sensory organs (baroreceptors and hypothalamus osmoreceptors), antidiuretic hormone (ADH or vasopressin), and the kidney.

Osmoreceptors in the hypothalamus are sensitive to the increased tonicity of serum, cause increase secretion of ADH from posterior pituitary. ADH secretion from hypothalamus through posterior pituitary is increased by :

• ↑ Angiotensin II (activation of Renin-Angiotensin-Activation System)
• ↑ Sympathetic stimulation
• ↑ Effective osmoles (Hypertonicity)
• ↓ Baroreceptor firing ( ↓effective intravascular volume)
• ↓ Right atrium stretching

ADH increases renal free water reabsorption from the collecting tubules and results in correction of plasma sodium toward the normal range. The vasopressin type 2 (V₂) receptor in the basolateral membrane of the collecting tubule acts as antidiuretic effect of ADH. Binding of ADH to V2 receptor intensifies action of intracellular cyclic adenosine monophosphate (cAMP) and results in insertion of water channel (aquaporin 2) into the luminal membrane and increasing in the number of aquaporin 2 mRNA level .As plasma water increases, plasma sodium concentration, osmolality, and ADH secretion decrease and the collecting tubule becomes impermeable to water, leads to excretion of free water and restoration of the plasma sodium concentration.

Mechanism of action of ADH , (ɔ) Image courtesy of WikiDoc.org, by "Dr. Saeedeh Kowsarnia"

Hyponatremia is defined as serum sodium less than 135 mEq/L (mmol/L).Hyponatremia is a water balance disorder which represents an imbalance in a ratio where total body water is more than total body solutes( total body sodium and total body potassium). 

Hyponatremia results from:

• Decreased renal excretion of water is the most cases of hyponatremia, secondary to persistent action of ADH.

• Blood sampling from a vein that is being infused with hypotonic medications.
• Older techniques (e.g., flame photometry) for sodium measurement, high levels of protein or triglyceride can cause false hyponatremia (Pseudohyponatremia).
• Hyperglycemia can also cause hyponatremia, osmotic water movement from cells into the blood, resulting in a relative decrease in serum sodium concentration in the absence of hypo-osmolality.

(for each 100-mg/dL increase in glucose concentration above 100 mg/dL The sodium concentration should be increased by approximately 1.6 to 2 mmol/L )

• Excess water intake is a rare cause of hyponatremia.In psychogenic polydipsia, ingesting large volumes (>15-20 L/day) of water results in hyponatremia, in spite of preserved renal function and diluting ability.
• Medications which interfere with urinary dilution (thiazide diuretics and nonsteroidal anti-inflammatory drugs [NSAIDs]).
• Clinical disorders ( congestive heart failure, nephrotic syndrome, cirrhosis) with the reduction in effective arterial blood volume, resulting in persistent ADH activity despite hypo-osmolar plasma.
• Acute or chronic renal failure results in reduced functional nephron mass, decreased glomerular filtration rate, and therefore decreased capacity for water excretion.

Hyponatremia represents as an excess of water relative to total body sodium, resulting from impaired water excretion by the kidneys or the depletion of sodium in excess of water.

Hypotonic (dilutional) hyponatraemia is classified by the extracellular volume status into hypo-, eu- and hyper-volemic hyponatremia.

Term	Definitions
Hyponatremia	Hyponatremia is defined as a serum sodium concentration < 135 mEq/L.
Hypotonic hyponatremia	Hyponatremia with low osmolality (hypotonic hyponatremia) is defined as hyponatremia with a serum osmolality below 280 mOsm/kg.
Hypertonic hyponatremia	Hyponatremia with high osmolality (hypertonic hyponatremia) is defined as hyponatremia with a serum osmolality greater than 295 mOsm/kg.
Isotonic hyponatremia	Hyponatremia with normal osmolality (Isotonic hyponatremia) is defined as hyponatremia with a serum osmolality ranging between 280-295 mOsm/kg.
Hyponatremia based on ECF volume
Hypovolemic hyponatremia	Hyponatremia plus decreased extracellular cellular fluid volume. Usually diagnosed by history and physical examinationshowing water depletion plus spot urine sodium <20 to 30 mmol/L, unless kidney is the source of sodium loss.
Euvolemic hyponatremia	Hyponatremia plus normal extracellular cellular fluid volume. Majority of cases are of this type. Usually diagnosed by spot urine sodium ≥ 20 to 30 mmol/L, unless secondarily sodium depleted.
Hypervolemia hyponatremia	Hyponatremia plus increased extracellular cellular fluid volume. Usually diagnosed by history and physical examinationshowing water retention plus spot urine sodium <20 to 30 mmol/L

Genetics

• Nephrogenic SIAD : Gain-of-function mutations of the V2 vasopressin receptor gene, AVPR2 causes hyponatremia