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

Hyponatremia is defined as serum sodium less than 135 mEq/L (mmol/L). Sodium is the major electrolyte which determines serum osmolality. Hyponatremia is a water balance disorder in which the ratio between sodium and water is disturbed. Water homeostasis is regulated mainly by two organs: hypothalamus by ADH secretion or thirst, kidney by water reabsorption or excretion. ADH is secreted due to alteration in serum osmolality or intravascular volume. Mechanisms in which different disorders cause hyponatremia involve ADH (secretion or action) and kidney function ( absorption or excretion). ADH secretion is increased by increased osmolality of serum or decreased effective intravascular volume.

Pathophysiology

Sodium is the main cation in the extracellular fluid, thus the plasma concentration of sodium is the 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.[1]

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 the serum.

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

Normal Range= 275–295 mosm /kg (mmol /kg) [3]

Normal range Osmolality versus Osmolarity
Sodium 135-145 mEq /L
  • Osmolality is described as measure of the osmoles (Osm) of solute per kilogram of solvent (osmol /kg or Osm /kg)[4]
  • Osmolarity is defined 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 ( magnocellular neurons). 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.[5]

ADH secretion from hypothalamus through posterior pituitary is increased by:[6][7]

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

Baroreceptors are in carotid sinus, Juxtaglomerular cell, atrial pressure receptors, hepatic volume receptors, cerebrospinal fluid volume receptors.

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.[8][9][10]

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 "Saeedeh Kowsarnia M.D"

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 acute hypovolemia compared to the response that is caused by hypertonicity.[11] ADH increases free water reabsorption from collecting tubules by V2 receptors and vascular resistance by V1 receptors. Replacement of losses with hypotonic fluid may cause further hyponatremia in addition to ADH effect. Hypovolemia caused by diarrhea induces sodium absorption from urine, results in low urine sodium. Vomiting caused hyponatremic hypovolemia which results in high urine sodium and low urine chloride due to bicarbonaturia and metabolic alkalosis.
  • Third spacing of fluid: Causes decreased intravascular volume which increases ADH secretion and water reabsorption. Decreased vascular volume induces 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 actions, water is absorbed more than sodium which causes hyponatremia.

Hypervolemic hyponatremia

  • Clinical disorders: In Congestive heart failure ( CHF) and cirrhosis, the reduction in effective arterial blood volume, resulting in persistent ADH activity despite hypoosmolar plasma. The ability to excrete water is also limited when the posterior pituitary continues to secrete ADH despite a low serum osmolality and plasma sodium concentration. Decreased effective arterial blood volume is sensed as hypovolemia which is the stronger stimulant of ADH secretion than osmolality of plasma. ADH is secreted without an osmotic stimulus if circulation is inadequate. Inpatients with cirrhosis decreased effective circulating volume is a result of arterial vasodilation of the splanchnic circulation, which is due to the increased endothelial release of nitric oxide. Moreover, large volume paracentesis in cases of refractory ascites can lead to more reduction of effective arterial volume, leading to postparacentesis circulatory dysfunction (PPCD) which worsens the renal failure and hyponatremia. [17]

Euvolemic hyponatremia

  • Syndrome of inappropriate antidiuresis: The most common cause of hyponatremia (euvolemic) due to either an increased level of ADH or gain-of-function mutation of the V2 receptor of ADH. Inappropriate secretion or action of ADH in the absence of osmotic or hemodynamic stimulus is called SIAD ( syndrome of inappropriate diuresis). Nephrogenic SIAD has the same presentation but ADH level is normal. Nearly 10% of SIAD is nephrogenic. Recently, hyponatremia has been found associated with COVID-19 infection [18] . Interleukin-6 (IL-6), which has been showed to be involved in the pathophysiology of COVID-19 and is released by monocytes and macrophages plays an important role in development of hyponatremia; it induces the non-osmotic release of vasopressin [19]. This along with the cytokine cascade cause numerous renal pathological changes, such as acute kidney injury (AKI), tubular necrosis, dysfunction of the kidney proximal tubule, glomerulopathy and electrolyte abnormalities.Also, renal cells expressing the receptors of the virus (ACE2), may explain the damage to kidney and subsequent electrolyte imbalances. Approximately 60% of patients with COVID-19 and watery diarrhea have moderate hyponatremia as well. [18]

Diagnostic criteria of SIAD [20] [21]
  • Urine concentration UOsm >100mOsm/kg , (NL=500-800 mOsm/kg )
  • Urine sodium >30 (20-40) mmol/L, with normal salt and water intake, (NL=20 mEq/L)
  • Clinical euvolemia

Supplemental criteria

  • Serum uric acid < 0.24 mmol/l (< 4 mg/dl), (NL= 2.4-6.0 mg/dL (female), 3.4-7.0 mg/dL (male) )
  • Serum urea < 3.6 mmol/l (< 21.6 mg/dl), (NL= 2.5 to 7.1 mmol/L, 7 to 20 mg/dL)
  • Failure to correct hyponatremia after 0.9% saline infusion
  • Fractional sodium excretion > 0.5%
  • Fractional urea excretion > 55%
  • Fractional uric acid excretion > 12%
  • Correction of hyponatremia through fluid restriction

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

mg/dl = molecular weight (MW) x mmol/l, for example MW for glucose and uric acid is 180 and 168 respectively

To review the drugs click here.

  • Reset osmostat: There is a downward resetting for ADH secretion by osmoreceptors, therefore, a lower level of plasma sodium concentration is required to completely suppress ADH release and water intake ( thirst). Pregnancy and drugs are the most common etiologies. In pregnancy, secretion of human chorionic gonadotropin is the main cause of resetting osmostat.

Puedohyponatremia

  • Hyperlipidemia, hyperproteinemia: Considerable elevations of either lipids or proteins in serum causes serum sodium to be measured lower than the actual total amount. Plasma osmolality is normal because the total number of solutes are the same but since the larger portion of plasma is occupied by excess lipids or protein, the measured serum sodium is lower especially with older techniques like flame photometry. Obstructive jaundice causes elevation of total serum cholesterol and high levels of lipoprotein X which causes the artefactual lower measurement of serum sodium concentration.
  • Blood sampling: Phlebotomy from a vein which is being infused with hypotonic medications cause serum sodium to be measured lower than the actual amount.
  • Hyperglycemia: Elevation of serum glucose causes hyponatremia by osmotic water movement from cells into the blood, which results in a relative decrease in serum sodium concentration. Calculation of serum osmolality and corrected serum sodium in hyperglycemia help to determine the actual cause of hyponatremia. 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. If the corrected serum sodium is within the normal range, hyponatremia can be explained by hyperglycemia. Lower or higher level of corrected serum sodium means hypotonic hyponatremia or hypernatremia, respectively.
  • Administration of mannitol or hypertonic radiocontrast can also result in nonhypotonic hyponatremia. [24]

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.

TermDefinitions[25][26][27]
HyponatremiaHyponatremia is defined as a serum sodium concentration < 135 mEq/L.
Hypotonic hyponatremiaHyponatremia with low osmolality (hypotonic hyponatremia) is defined as hyponatremia with a serum osmolality below 280 mOsm/kg.
Hypertonic hyponatremiaHyponatremia with high osmolality (hypertonic hyponatremia) is defined as hyponatremia with a serum osmolality greater than 295 mOsm/kg.
Isotonic hyponatremiaHyponatremia 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 hyponatremiaHyponatremia 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 hyponatremiaHyponatremia 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 hyponatremiaHyponatremia 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 antidiuresis):[28] Gain-of-function mutations of the V2 vasopressin receptor gene (AVPR2) causes hyponatremia.
  • Pseudohypoaldosteronism
  • Aldosterone Biosynthetic Defects
  • Gittleman syndrome
  • Bartter syndrome

Associated Conditions

References

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