Hyponatremia pathophysiology: Difference between revisions

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*  '''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 <ref>{{Cite journal|year=1987|title=Osmoregulation and control of vasopressin secretion in healthy humans|journal=[[The American journal of physiology]]|volume=253|issue=5 Pt 2|pages=R671–R678|doi=10.1152/ajpregu.1987.253.5.R671|pmid=3318505|author=[[P. H. Baylis]]|month=November}}</ref>. 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.   
*  '''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 <ref>{{Cite journal|year=1987|title=Osmoregulation and control of vasopressin secretion in healthy humans|journal=[[The American journal of physiology]]|volume=253|issue=5 Pt 2|pages=R671–R678|doi=10.1152/ajpregu.1987.253.5.R671|pmid=3318505|author=[[P. H. Baylis]]|month=November}}</ref>. 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.
* '''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.  


* '''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 <ref>{{Cite journal
* '''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 <ref>{{Cite journal

Revision as of 17:41, 15 May 2018

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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 [1] 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) [2]

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

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)[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. 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 (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 [8][9] 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 [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.
  • 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 [12]. In contrast, loop diuretics decrease the action of ADH on medullary part of collecting tubules by impairing medullary gradient [13] .
  • Renal loss: Inappropriately loss of sodium in urine causes hypovolemia and ADH secretion.
    • Salt-wasting nephropathy: Renal tubular dysfunction causes hyponatremia especially when sodium intake is reduced. The causes include Interstitial nephropathies, reflux nephropathies, recovery phase of ATN, medullary cystic disease and post-obstructive uropathies.
    • Bicarbonaturia: Renal tubular acidosis and metabolic alkalosis causes loss of bicarbonate and sodium in urine to balance charges in urine.
    • Cerebral salt-wasting syndrome: Subarachnoid hemorrhage, ischemic stroke, spontaneous intracerebral hemorrhage (ICH), craniotomy, encephalitis, meningitis and head trauma are considered the most common etiologies. The pathophysiology of CSW syndrome is not completely understood. Decreased sympathetic activity to the kidneys and Increased brain natriuretic peptide are the most accepted hypothesis. Renin-aldosterone is decreased due to reduced sympathetic stimulation[14] . Increased natriuretic peptides causes sodium loss( natriuresis )by increasing GFR and preventing sodium reabsorption in the collecting duct [15].Natriuretic peptides inhibit aldosterone and ADH action. Reducing sympathetic outflow by natriuretic peptides decreases aldosterone secretion which lowers sodium level further [16].
    • Osmotic diuresis: Urinary excretion of osmatically active solutes causes volume depletion and hyponatremia. Glucosoria and ketonuria in DKA and HHS obligates sodium and water loss even in the presence of hypovolemia.
    • Mineralocorticoid deficiency: Adrenal insufficiency (aldosterone deficiency, primary ) leads to renal sodium loss and volume depletion, causing release of ADH due to hypovolemia. Patients typically present with hypovolemia, hyponatremia, hyperkalemia, decreased bicarbonate and increased urine sodium and inappropriate renal response in the setting of volume depletion.

Hypervolemic hyponatremia

  • Renal disease: Chronic or acute renal failure results in reduced functional nephron mass, decreased glomerular filtration rate (GFR) and therefore decreased capacity for water excretion. Nephrotic syndrome causes reduced effective circulatory volume and edema which results in increased ADH effect.
  • Clinical disorders: In Congestive heart failure( CHF) and cirrhosis ,the reduction in effective arterial blood volume, resulting in persistent ADH activity despite of 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 increased endothelial release of nitric oxide.

Euvolemic hyponatremia

  • Syndrome of inappropriate antidiuresis: The most common cause of hyponatremia (euvolemic) due to either 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).
Diagnostic criteria of SIAD [17] [18]
  • serum sodium <135 mEq/L
  • Plasma osmolality <275 mOsm/kg , ( NL=275–295 mOsm/kg)
  • urine concentration UOsm >100mOsm/kg H2O, (NL=500-800 mOsm/kg H2O)
  • Urine sodium >30 (20-40) mmol/L, with normal salt and water intake, (NL=20 mEq/L)
  • Clinical euvolemia
  • Exclusion of glucocorticoid deficiency or hypothyroidism

Supplemental criteria

  • Serum uric acid < 0.24 mmol/l (< 4 mg/dl)
  • Serum urea < 3.6 mmol/l (< 21.6 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

  • Decreased renal excretion of water:
  • Excess water intake: In exercise-associated hyponatremia, increased level of ADH due to hypovolemia and excess free water intake cause hyponatremia. In primary polydipsia, ingesting large volumes (>15-20 L/day) of water results in hyponatremia, in spite of normal renal function and diluting ability.
  • Hormonal: Glucocorticoids have an inhibitory effect on ADH release by the posterior pituitary so cortisol deficiency induces ADH secretion. Thyroid hormone deficiency especially primary hypothyroidism causes hyponatremia by elevated level of ADH and decreased GFR therefore decreased ability to excrete diluted urine [19] [20] .Secondary adrenal insufficiency (hypopituitarism), presents with features of SIAD ( euvolemic hyponatremia).
  • 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.
  • “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).
  • Reset osmostat:

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 )

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[21][22][23]
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 anti diuresis) [24] : 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

References

  1. Sperelakis, Nick (2012). Cell physiology sourcebook : essentials of membrane biophysics. London, UK Waltham, MA, USA: Elsevier/Academic Press. ISBN 978-0-12-387738-3.
  2. Purssell, Roy A.; Pudek, Morris; Brubacher, Jeffrey; Abu-Laban, Riyad B. (2001). "Derivation and validation of a formula to calculate the contribution of ethanol to the osmolal gap". Annals of Emergency Medicine. 38 (6): 653–659. doi:10.1067/mem.2001.119455. ISSN 0196-0644.
  3. Hooper, Lee; Abdelhamid, Asmaa; Ali, Adam; Bunn, Diane K; Jennings, Amy; John, W Garry; Kerry, Susan; Lindner, Gregor; Pfortmueller, Carmen A; Sjöstrand, Fredrik; Walsh, Neil P; Fairweather-Tait, Susan J; Potter, John F; Hunter, Paul R; Shepstone, Lee (2015). "Diagnostic accuracy of calculated serum osmolarity to predict dehydration in older people: adding value to pathology laboratory reports". BMJ Open. 5 (10): e008846. doi:10.1136/bmjopen-2015-008846. ISSN 2044-6055.
  4. Erstad BL (2003). "Osmolality and osmolarity: narrowing the terminology gap". Pharmacotherapy. 23 (9): 1085–6. PMID 14524639.
  5. Verbalis, J. G. (2007). "How Does the Brain Sense Osmolality?". Journal of the American Society of Nephrology. 18 (12): 3056–3059. doi:10.1681/ASN.2007070825. ISSN 1046-6673.
  6. G. L. Robertson (1987). "Physiology of ADH secretion". Kidney international. Supplement. 21: S20–S26. PMID 3476800. Unknown parameter |month= ignored (help)
  7. L. Share (1967). "Vasopressin, its bioassay and the physiological control of its release". The American journal of medicine. 42 (5): 701–712. PMID 5337374. Unknown parameter |month= ignored (help)
  8. Holmes, Cheryl L; Landry, Donald W; Granton, John T (2003). Critical Care. 7 (6): 427. doi:10.1186/cc2337. ISSN 1364-8535. Missing or empty |title= (help)
  9. Holmes, Cheryl L; Landry, Donald W; Granton, John T (2003). Critical Care. 7 (6): 427. doi:10.1186/cc2337. ISSN 1364-8535. Missing or empty |title= (help)
  10. Kwon, Tae-Hwan; Hager, Henrik; Nejsum, Lene N.; Andersen, Marie-Louise E.; Fr[oslash]ki[aelig ]r, J[oslash]rgen; Nielsen, S[oslash]ren (2001). "Physiology and pathophysiology of renal aquaporins". Seminars in Nephrology. 21 (3): 231–238. doi:10.1053/snep.2001.21647. ISSN 0270-9295.
  11. P. H. Baylis (1987). "Osmoregulation and control of vasopressin secretion in healthy humans". The American journal of physiology. 253 (5 Pt 2): R671–R678. doi:10.1152/ajpregu.1987.253.5.R671. PMID 3318505. Unknown parameter |month= ignored (help)
  12. K. R. Cesar & A. J. Magaldi (1999). "Thiazide induces water absorption in the inner medullary collecting duct of normal and Brattleboro rats". The American journal of physiology. 277 (5 Pt 2): F756–F760. PMID 10564239. Unknown parameter |month= ignored (help)
  13. V. L. Szatalowicz, P. D. Miller, J. W. Lacher, J. A. Gordon & R. W. Schrier (1982). "Comparative effect of diuretics on renal water excretion in hyponatraemic oedematous disorders". Clinical science (London, England : 1979). 62 (2): 235–238. PMID 7053922. Unknown parameter |month= ignored (help)
  14. Kim, Dong Ki; Joo, Kwon Wook (2009). "Hyponatremia in Patients with Neurologic Disorders". Electrolytes & Blood Pressure. 7 (2): 51. doi:10.5049/EBP.2009.7.2.51. ISSN 1738-5997.
  15. Damaraju, Sriram Chandra; Rajshekhar, Vedantam; Chandy, Mathew J. (1997). "Validation Study of a Central Venous Pressure-based Protocol for the Management of Neurosurgical Patients with Hyponatremia and Natriuresis". Neurosurgery. 40 (2): 312–317. doi:10.1097/00006123-199702000-00015. ISSN 0148-396X.
  16. . doi:10.3275/7290. Missing or empty |title= (help)
  17. Natasa Janicic & Joseph G. Verbalis (2003). "Evaluation and management of hypo-osmolality in hospitalized patients". Endocrinology and metabolism clinics of North America. 32 (2): 459–481. PMID 12800541. Unknown parameter |month= ignored (help)
  18. W. B. Schwartz, W. Bennett, S. Curelop & F. C. Bartter (2001). "A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. 1957". Journal of the American Society of Nephrology : JASN. 12 (12): 2860–2870. PMID 11729259. Unknown parameter |month= ignored (help)
  19. P. H. Schmitz, P. H. de Meijer & A. E. Meinders (2001). "Hyponatremia due to hypothyroidism: a pure renal mechanism". The Netherlands journal of medicine. 58 (3): 143–149. PMID 11246114. Unknown parameter |month= ignored (help)
  20. R. W. Schrier & D. G. Bichet (1981). "Osmotic and nonosmotic control of vasopressin release and the pathogenesis of impaired water excretion in adrenal, thyroid, and edematous disorders". The Journal of laboratory and clinical medicine. 98 (1): 1–15. PMID 7019365. Unknown parameter |month= ignored (help)
  21. Laczi, F. (2008). "[Etiology, diagnostics and therapy of hyponatremias]". Orv Hetil. 149 (29): 1347–54. doi:10.1556/OH.2008.28409. PMID 18617466. Unknown parameter |month= ignored (help)
  22. Douglas, I. (2006). "Hyponatremia: why it matters, how it presents, how we can manage it". Cleve Clin J Med. 73 Suppl 3: S4–12. PMID 16970147. Unknown parameter |month= ignored (help)
  23. Verbalis, JG.; Goldsmith, SR.; Greenberg, A.; Korzelius, C.; Schrier, RW.; Sterns, RH.; Thompson, CJ. (2013). "Diagnosis, evaluation, and treatment of hyponatremia: expert panel recommendations". Am J Med. 126 (10 Suppl 1): S1–42. doi:10.1016/j.amjmed.2013.07.006. PMID 24074529. Unknown parameter |month= ignored (help)
  24. Powlson, Andrew S.; Challis, Benjamin G.; Halsall, David J.; Schoenmakers, Erik; Gurnell, Mark (2016). "Nephrogenic syndrome of inappropriate antidiuresis secondary to an activating mutation in the arginine vasopressin receptor AVPR2". Clinical Endocrinology. 85 (2): 306–312. doi:10.1111/cen.13011. ISSN 0300-0664.

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