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.

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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]

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

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

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

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

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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 thus plasma osmolarity and plasma osmolality would be the same but osmolality is independent of temperature and pressure so it's the more stable unite of measurment)
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)
Serum osmolality	275–295 mosm /kg (mmol /kg) †

‡ Mmol and Meq are the same for univalent ions like sodium, potassium

† mOsmol/kg = n x mmol/L, for Na⁺, Cl^-, Ca²⁺, urea, and glucose, 1 mmol/L equals 1 mOsmol/kg because n=1 , for NaCl n=2

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

Osmoreceptors in the hypothalamus are sensitive to the increased or decreased tonicity of serum. The primary brain osmoreceptors are located outside the blood-brain barrier in the lamina terminalis. Primary osmoreceptors are connected to brain areas responsible for ADH secretion and thirst by neuronal projections. Osmoreceptors can both stimulate and inhibit ADH secretion and thirst in response to hyper-and hypotonicity of serum, respectively .

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 which 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 the antidiuretic effect of ADH. Binding of ADH to V2 receptor intensifies the action of intracellular cyclic adenosine monophosphate (cAMP) which results in insertion of water channel (aquaporin 2) into the luminal membrane and increasing the numbers 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.

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).

Pathogenesis

Hyponatremia occurs when the release of ADH (AVP) is increased either physiologically appropriate due to decreased effective circulating volume, or inappropriately due to no physiologic reason. In response to the release of ADH, urine volume decreases and hyponatremia will develop especially when water intake exceeds urinary and insensible losses of water. Patients are typically classified based on their total body sodium as hypovolemic, euvolemic, and hypervolemia.

Hypovolemic hyponatremia

• Volume loss: GI loss, bleeding and insensible loss cause solute and water loss simultaneously which leads to the rise in ADH secretion. A considerable reduction in effective arterial blood volume increase release of ADH by baroreceptors rather than osmoreceptors. There is a marked release in ADH secretion by hypovolemia compared to the one that is caused by hypertonicity . Replacement of losses with hypotonic fluid may cause further hyponatremia in addition to ADH effect. Diarrhea increases sodium absorption from urine in contrast to vomiting which results in high urine sodium and low urine chloride due to bicarbonaturia and to metabolic alkalosis.

• Third spacing of fluid: Causes decreased intravascular volume which increases ADH secretion and water reabsorption. Decreased vascular volume cause increased the activity of the renin-angiotensin-aldosterone system. Aldosterone increases water and sodium absorption by the kidney. As a net result of ADH and aldosterone action, water is absorbed more than sodium which causes hyponatremia.

• Diuretics: Thiazides increase water reabsorption and water permeability of medullary part of collecting tubules which is independent of ADH action. Excretion of sodium and potassium to the urine causes further hyponatremia . In contrast, loop diuretics decrease the action of ADH on medullary part of collecting tubules by impairing medullary gradient .
• Renal loss:

Puedohyponatremia

· 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 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

Hypervolemic hyponatremia

• 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 normal renal function and diluting ability.

• Acute or chronic renal failure results in reduced functional nephron mass, decreased glomerular filtration rate and therefore decreased capacity for water excretion.

• 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. The ability to excrete water is also limited when the posterior pituitary continues to secrete ADH (AVP) despite a low plasma sodium concentration. ADH is secreted without an osmotic stimulus if circulation is inadequate, as in patients with hypovolemia or heart or liver disease. “Inappropriate secretion” of ADH occurs in the absence of both osmotic and hemodynamic stimulus. Affected patients have the syndrome of inappropriate antidiuretic hormone secretion (SIADH).

Euvolemic hyponatremia

• Decreased renal excretion of water is the most cases of hyponatremia, secondary to persistent action of ADH or gain-of-function mutation of the V2 receptor of ADH.

• Hormonal cortisol which has an inhibitory effect on ADH release. Adrenal insufficiency causes increased ADH level.

• Medications cause hyponatremia with different mechanisms like interfering with urinary dilution (thiazide diuretics and nonsteroidal anti-inflammatory drugs [NSAIDs]), increasing ADH secretion or persisting ADH effect.

Hyponatremia represents 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) hyponatremia 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 (syndrome of inappropriate anti diuresis)  : Gain-of-function mutations of the V2 vasopressin receptor gene (AVPR2) causes hyponatremia.
• Pseudohypoaldosteronism
• Aldosterone Biosynthetic Defects
• Gittleman syndrome
• Bartter syndrome

Associated Conditions

• Fanconi syndrome
• Renal tubular acicosis