Biochemistry, Hypertonicity


Article Author:
Kenia Maldonado


Article Editor:
Shamim Mohiuddin


Editors In Chief:
Kranthi Sitammagari
Mayank Singhal


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Trevor Nezwek
Radia Jamil
Patrick Le
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Hassam Zulfiqar
Hussain Sajjad
Steve Bhimji
Muhammad Hashmi
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Sarosh Vaqar
Mark Pellegrini
James Hughes
Beata Beatty
Beenish Sohail
Nazia Sadiq
Hajira Basit
Phillip Hynes


Updated:
5/6/2019 12:00:22 AM

Introduction

Tonicity

Tonicity is the capability of a solution to modify the volume of cells by altering their water content. Cells swell by gaining water (hypotonicity) or shrink by losing water (hypertonicity) through osmotic pressure differences between the intracellular compartment (IC) and the solution tested. Solutions are isotonic when the volume of cells suspended in them does not change by osmotic fluid transfers.[1]

Osmosis

Osmosis refers to water movement, which usually moves in favor of an osmotic gradient, so that water flows where there is higher osmotic concentration across a selectively permeable membrane.

Osmolarity

Osmolarity is the term used for describing the concentration of solutes within a fluid. Meanwhile, the words isotonic, hypertonic and hypotonic compare the osmolarity of a cell to the osmolarity of the extracellular fluid around it. Hyperosmolarity doesn't always mean hypertonicity because this depends on the solutes. For example, solutes such as Na+ and glucose need transporters, they contribute to serum tonicity and are termed effective osmoles (contributing to osmolarity), while urea and ethanol easily pass through cell membranes, thus contributing to serum osmolality but not tonicity.[2]

Fundamentals

Disturbances in tonicity are the major clinical disorders affecting volume, proper function and survival of body cell. It causes water movement into or out of cells, thereby diluting or concentrating intracellular ions.[3] These alterations in the homeostasis of the cells lead to a set of mechanisms to maintain their normal size as well as their functioning. Hyperosmolality itself alters several intracellular processes including cell volume regulation, cell cycle, intracellular ion homeostasis, macromolecular and nucleic acid stability and can induce apoptosis.[4]

Issues of Concern

Hyperglycemic and hypernatremic states are the main responsible for the alteration in tonicity. Cell shrinking secondary to hypertonicity can cause severe clinical manifestations and even death.[1] Assessment of the clinical circumstances along with serum and urine studies help to determine the etiology and to aim for the right management.[2]

Cellular

In a hypertonic environment, cells lose water through osmotic pressure differences using membrane proteins called aquaporin channels, to go to the higher concentration medium. Because cells are permeable to water, they shrink and elevate the concentration of intracellular solutes. The survival mechanisms used by cells include accumulation of organic osmolytes and increased expression of proteins through numerous pathways, resulting in osmotolerance.[5] The shrinkage of cells generates stress that is adjusted by some mechanisms due to the work of the Na+,K+-ATPase (in steady conditions). "Fast" volume regulation due to rapid activation of membrane ion transporters and "slow" adaptation to chronic changes in extracellular osmolarity involving modifications in gene expression and intracellular organic osmolyte content.[6]

In steady conditions, a fundamental property of cells is that they contain a significant amount of large-molecular-weight anionic colloids (mostly proteins and organic phosphates) to which the plasma membrane is impermeable.[7] So the existence of these proteins in only one of the compartments that are impermeable to them produces a higher concentration, thus generating osmotic forces between the extracellular and intracellular compartment (this is known as Donnan effect).

Molecular

Hypertonicity denotes relative excess of the solute with extracellular distribution over body water regardless of whether body water is normal, reduced or excessive. The gain of extracellular solutes leads to the osmotic exit of water from the intracellular compartment to dilute the extracellular solutes. Sodium salts, which includes sodium chloride and sodium bicarbonate, are the major extracellular solutes and routinely indicates hypertonicity.[8]

Under hypertonic conditions, ions such as Na, Cl, and K accumulate in the cytosol and get exchanged for compatible organic osmolytes that do not perturb intracellular protein structure or function.[9] A fast response gets driven by the fast activation of Na+,K+,2Cl- co-transporter and the Na+/H+ exchanger which couples to Cl-/H2CO3- anion exchanger.

On the other hand, TonEBP (tonicity-responsive enhancer binding protein) which is also known as NFAT5 or OREBP, is a transcription factor that can promote cellular accumulation of organic osmolytes in the hypertonic renal medulla by stimulating expression of its target genes,[10] but it is also abundantly expressed in brain, heart, liver and activated T-cells.[11]

Additionally, there is evidence that osmotic stress elicits a morphological disruption of the transverse tubular system (a continuation of the surface membrane that forms a junction with the sarcoplasmic reticulum which is known for its calcium storage) in skeletal muscle fibers. It is the primary interface between the myoplasm and the extracellular environment and these arrangements are essential to produce muscle contraction.[12]

Function

Regulation of osmolarity and volume play an essential role in maintaining body water balance and tonicity.[2]

The acute adaptation to hypertonicity consists in ''regulatory volume increase'' (RVI). It requires the activation of the Na+,K+,2Cl- co-transporter and the Na+/H+ exchanger which couples to the Cl-/H2CO3- anion exchanger. These last two brings NaCl and KCl into the cell and H2CO3 out of it. This H2CO3 is then converted to CO2 to go back to the pool of H+ and HCO3- inside the cells, followed by the thermodynamically obliged movement of water. Sodium ion entering the cells is extruded through Na/K ATPase in exchange for potassium, being potassium chloride which is the final salt gained intracellularly in hypertonicity.[1]

Meanwhile, in a chronic adaptation, a general response to hypertonicity is the activation of the transcription factor tonicity (TonEBP), leading to cells to increase the expression of organic osmolyte transporters and enzymes. Some of the transcriptions of genes that TonEBP produces are aldose reductase (AR), betaine/GABA transporter(BGT1), sodium myoinositol transporter (SMIT) and taurine transporter (TauT). The transcription of Hsp70, urea transporters (UTA1 and -2) and water channel aquaporin-2 (AQP2) which is a water channel protein when activated, increases cell membrane water permeability, is also activated by TonEBP.[13]

Mechanism

Cells that are shrunken by hypertonicity responds initially with RVI. It increases the uptake of inorganic salts and the osmotic influx of water, but this results in high intracellular inorganic salt concentration that perturbs cells function and structure. So to counteract this, cells activate TonEBP for the transcription of genes to code for aldose reductase (for the synthesis of sorbitol) and transporters of betaine, inositol, and taurine, thus accumulating large amounts of organic osmolytes which are important because they have an osmoprotective effect.

Most cells in mammals are generally not stressed by hypertonicity because of the close control of the concentration of NaCl in virtually all extracellular body fluids. The renal inner medulla is a striking exception.[14] Because of its urinary concentrating mechanism, it has routine exposure to extremely high concentrations of sodium chloride (NaCl) and urea. The adaptation of medullary cells to hyperosmotic stress involves acute cellular efflux of water, cell shrinkage by NaCl, chronic accumulation of compatible organic osmolytes and acute activation of immediate-early and heat shock genes.[15] Renal medullary cells do not restrict this mechanism, which also happens to cells in other tissues when they get exposed to pathologic conditions that produce hypertonic states.

Testing

The predominant clinical syndromes of hypertonicity are hypernatremia and hyperglycemia.[8] Rises in tonicity from changes in body water, body solute or both can be assessed testing osmolarity in serum and urine and correlating it with the level of electrolytes in these two compartments to establish the cause of the impairment. The serum osmolarity normal range is 280 to 295mOsm/ kgH2O and normal urine osmolality is from 50mOsm/kgH2O to 1400mOsm/kgH2O.[2] Normal serum sodium is 135 to 145mmol/L, and urinary sodium reference range varies with the diet.[16]

Pathophysiology

Tonicity is under tightly regulation by the equilibrium between water intake and water excretion.[2] There are normal conditions where water loss occurs like in respiration, gastrointestinal fluids,  urine, and skin. The problem occurs when patients are unable to replete those losses. That's why the osmoreceptors in the hypothalamus sense the increase in serum tonicity and stimulate thirst and in consequence individuals increase their intake of water. Just 1% of the change in tonicity is enough to produce ADH release, but it needs a greater than 10% fall in extracellular volume to be released. ADH acts on V2 receptors in the principal cells of the collecting tubules in kidneys and inserts aquaporins for water movement from the tubules to the hypertonic interstitium. Kidneys concentrating urine is the primary reaction to water loss, to retain water for the dilution that excess of solutes.

One of the cardinal manifestations of hyperglycemic crisis is hypertonicity.[17] The excess of glucose in the extracellular fluid has a hypertonic effect; hyperglycemia also produces an osmotic diuresis that makes water loss exceed the losses of sodium and potassium. Because of that, there is an elevation in sodium concentration. Hyperglycemia also produces thirst as a defense mechanism to reestablish its water content and tonicity, but this isn't as effective as in hypernatremia.

Studies have shown that the TonEBP upregulates the expression of AR under high-glucose conditions in diabetic microvascular complication, particularly diabetic nephropathy.[18] Hyperglycemia stimulates the aldose reductase production in cells that express that enzyme. This enzyme catalyzes the reaction of glucose to sorbitol. Sorbitol cannot cross cell membranes, and its accumulation generates osmotic stress on cells by drawing water into tissues, being this one of the mechanisms that glucose produces disturbance to them. AR is present in tissues such as nerve, retina, lens, glomerulus and vascular cells.[19]

Other cells like astrocytes play a major role in defense of brain volume in acute states of tonicity variations. Immediate adaptation to brain shrinking includes movement of fluid from the cerebrospinal fluid into the astrocytes, but this is a limited adaptive mechanism because the main adaptation occurs by RVI.

Clinical Significance

Acute hypertonicity most often affects the extremes of life (children-elderly), and patients may develop fever, nausea, and vomiting. In children, symptoms can range from irritability, restlessness, muscular twitching to hyperreflexia and seizures; and in the elderly lethargy, delirium and coma, but rarely develop seizures. On the other hand, chronic hypertonicity may manifest with only subtle neurological changes because it has more time to adapt to the medium, even when hypertonicity is severe.[8]

Conditions causing hypernatremia are due to inadequate water intake such as:

  • Lack of water sources, a central nervous system disorder compromising neural pathways of thirst
  • Tracheal intubation, and sedation, dementia
  • Delirium, paranoia, severe depression
  • Degenerative processes like Parkinson's disease
  • Diabetes insipidus, etc.

It can also result from excessive water loss like[8]:

  • Gastrointestinal losses
  • Excessive sweating
  • Mechanical ventilation, glucosuria
  • Diabetes insipidus
  • Genetic mutation of V2 receptor gene or aquaporin 2 gene
  • Drugs etc.

Glucose as an osmotically active substance results in water movement out of the cells and subsequently in a reduction of serum sodium levels by dilution. Therefore it is crucial to correct serum sodium for hyperglycemia, which is calculated by adding to measured [Na] 1.6 mmol/L for every 100 mg/dL (5.55 mmol/L) increment of serum glucose above normal,[20] but sometimes laboratories already report the corrected serum sodium. Under other conditions, uncontrolled hyperglycemic patients produce osmotic diuresis losing water and then causing a hypovolemic state presenting with signs such as orthostatic hypotension and increased pulse rate, decreased skin turgor, flat neck veins, dry mucous membranes, etc. So, it also can lead to hypernatremia, if there is not sufficient replacement of this water loss. For that reason, in patients like for example with diabetes mellitus, sodium concentration can be variable, demonstrating the hyperglycemia-induced water movement out of the cells that lower Na and the glucosuria induced osmotic diuresis, which can raise it.


Interested in Participating?

We are looking for contributors to author, edit, and peer review our vast library of review articles and multiple choice questions. In as little as 2-3 hours you can make a significant contribution to your specialty. In return for a small amount of your time, you will receive free access to all content and you will be published as an author or editor in eBooks, apps, online CME/CE activities, and an online Learning Management System for students, teachers, and program directors that allows access to review materials in over 500 specialties.

Improve Content - Become an Author or Editor

This is an academic project designed to provide inexpensive peer-reviewed Apps, eBooks, and very soon an online CME/CE system to help students identify weaknesses and improve knowledge. We would like you to consider being an author or editor. Please click here to learn more. Thank you for you for your interest, the StatPearls Publishing Editorial Team.

Biochemistry, Hypertonicity - Questions

Take a quiz of the questions on this article.

Take Quiz
A 65-year-old man is taken to the emergency department after a tonic-clonic seizure. At the time of admission, he has confusion and headache. His blood pressure is 112/78 mmHg, and the temperature is 37.2 C. Examination shows mild muscular hypertonia, and there are no focal neurologic signs. He has a past medical history of depression treated with escitalopram. Serum osmolality is 269 mOsm/L, serum sodium is 119 mEq/L, and urinary osmolality is 168 mOsm/L. The patient is diagnosed with the syndrome of inappropriate antidiuretic hormone secretion and is hospitalized. On the third day, his natremia is 133 mEq/L. At this point, which of the following is most likely to happen in the erythrocytes if a 3% sodium chloride solution is added to a sample of his blood?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 48-year-old man comes to the office because he has had nocturia for about three weeks and feels thirsty all the time. He has a past medical history of hypertension, and his medication includes amlodipine. Laboratory results reveal serum sodium: 152 mEq/L, serum osmolality: 318 mEq/L, and urine osmolality: 125 mEq/L, fasting glucose is 88 mg/dL. Which of the following is the preferred initial therapy for this patient?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up
A 65-year-old woman goes to the office for poor vision at night that is getting worse these past months. The last time she went to a doctor was 6 years ago. Ophthalmoscopy reveals macular edema, exudates, blot hemorrhages. Hemoglobin A1c is 1%1. The provider explains that her microvascular complication is due to the hyperglycemia. Which of the following choice is the general response to this state?



Click Your Answer Below


Would you like to access teaching points and more information on this topic?

Improve Content - Become an Author or Editor and get free access to the entire database, free eBooks, as well as free CME/CE as it becomes available. If interested, please click on "Sign Up" to register.

Purchase- Want immediate access to questions, answers, and teaching points? They can be purchased above at Apps and eBooks.


Sign Up

Biochemistry, Hypertonicity - References

References

Argyropoulos C,Rondon-Berrios H,Raj DS,Malhotra D,Agaba EI,Rohrscheib M,Khitan Z,Murata GH,Shapiro JI,Tzamaloukas AH, Hypertonicity: Pathophysiologic Concept and Experimental Studies. Cureus. 2016 May 2;     [PubMed]
Betten R,Scharner B,Probst S,Edemir B,Wolff NA,Langelueddecke C,Lee WK,Thévenod F, Tonicity inversely modulates lipocalin-2 (Lcn2/24p3/NGAL) receptor (SLC22A17) and Lcn2 expression via Wnt/β-catenin signaling in renal inner medullary collecting duct cells: implications for cell fate and bacterial infection. Cell communication and signaling : CCS. 2018 Nov 7;     [PubMed]
Lado MG,Sheu SS,Fozzard HA, Effects of tonicity on tension and intracellular sodium and calcium activities in sheep heart. Circulation research. 1984 May;     [PubMed]
Hoffmann EK,Lambert IH,Pedersen SF, Physiology of cell volume regulation in vertebrates. Physiological reviews. 2009 Jan;     [PubMed]
Mongin AA,Orlov SN, Mechanisms of cell volume regulation and possible nature of the cell volume sensor. Pathophysiology : the official journal of the International Society for Pathophysiology. 2001 Dec;     [PubMed]
Neuhofer W,Beck FX, Cell survival in the hostile environment of the renal medulla. Annual review of physiology. 2005;     [PubMed]
Bortner CD,Cidlowski JA, Absence of volume regulatory mechanisms contributes to the rapid activation of apoptosis in thymocytes. The American journal of physiology. 1996 Sep;     [PubMed]
Schulze Blasum B,Schröter R,Neugebauer U,Hofschröer V,Pavenstädt H,Ciarimboli G,Schlatter E,Edemir B, The kidney-specific expression of genes can be modulated by the extracellular osmolality. FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2016 Oct;     [PubMed]
Woo SK,Lee SD,Kwon HM, TonEBP transcriptional activator in the cellular response to increased osmolality. Pflugers Archiv : European journal of physiology. 2002 Aug;     [PubMed]
Lee SD,Choi SY,Lim SW,Lamitina ST,Ho SN,Go WY,Kwon HM, TonEBP stimulates multiple cellular pathways for adaptation to hypertonic stress: organic osmolyte-dependent and -independent pathways. American journal of physiology. Renal physiology. 2011 Mar;     [PubMed]
Umenishi F,Yoshihara S,Narikiyo T,Schrier RW, Modulation of hypertonicity-induced aquaporin-1 by sodium chloride, urea, betaine, and heat shock in murine renal medullary cells. Journal of the American Society of Nephrology : JASN. 2005 Mar;     [PubMed]
Burg MB,Kwon ED,Kültz D, Regulation of gene expression by hypertonicity. Annual review of physiology. 1997;     [PubMed]
Hernández-Ochoa EO,Robison P,Contreras M,Shen T,Zhao Z,Schneider MF, Elevated extracellular glucose and uncontrolled type 1 diabetes enhance NFAT5 signaling and disrupt the transverse tubular network in mouse skeletal muscle. Experimental biology and medicine (Maywood, N.J.). 2012 Sep;     [PubMed]
Rondon-Berrios H,Argyropoulos C,Ing TS,Raj DS,Malhotra D,Agaba EI,Rohrscheib M,Khitan ZJ,Murata GH,Shapiro JI,Tzamaloukas AH, Hypertonicity: Clinical entities, manifestations and treatment. World journal of nephrology. 2017 Jan 6;     [PubMed]
Kitabchi AE,Umpierrez GE,Miles JM,Fisher JN, Hyperglycemic crises in adult patients with diabetes. Diabetes care. 2009 Jul;     [PubMed]
Giacco F,Brownlee M, Oxidative stress and diabetic complications. Circulation research. 2010 Oct 29;     [PubMed]
Hu B,Han Q,Mengke N,He K,Zhang Y,Nie Z,Zeng H, Prognostic value of ICU-acquired hypernatremia in patients with neurological dysfunction. Medicine. 2016 Aug;     [PubMed]
Agrawal V,Agarwal M,Joshi SR,Ghosh AK, Hyponatremia and hypernatremia: disorders of water balance. The Journal of the Association of Physicians of India. 2008 Dec;     [PubMed]
Kim SJ,Kim H,Park J,Chung I,Kwon HM,Choi WS,Yoo JM, Tonicity response element binding protein associated with neuronal cell death in the experimental diabetic retinopathy. International journal of ophthalmology. 2014;     [PubMed]
Liamis G,Liberopoulos E,Barkas F,Elisaf M, Diabetes mellitus and electrolyte disorders. World journal of clinical cases. 2014 Oct 16;     [PubMed]

Disclaimer

The intent of StatPearls is to provide practice questions and explanations to assist you in identifying and resolving knowledge deficits. These questions and explanations are not intended to be a source of the knowledge base of all of medicine, nor is it intended to be a board or certification review of PA-Hospital Medicine. The authors or editors do not warrant the information is complete or accurate. The reader is encouraged to verify each answer and explanation in several references. All drug indications and dosages should be verified before administration.

StatPearls offers the most comprehensive database of free multiple-choice questions with explanations and short review chapters ever developed. This system helps physicians, medical students, dentists, nurses, pharmacists, and allied health professionals identify education deficits and learn new concepts. StatPearls is not a board or certification review system for PA-Hospital Medicine, it is a learning system that you can use to help improve your knowledge base of medicine for life-long learning. StatPearls will help you identify your weaknesses so that when you are ready to study for a board or certification exam in PA-Hospital Medicine, you will already be prepared.

Our content is updated continuously through a multi-step peer review process that will help you be prepared and review for a thorough knowledge of PA-Hospital Medicine. When it is time for the PA-Hospital Medicine board and certification exam, you will already be ready. Besides online study quizzes, we also publish our peer-reviewed content in eBooks and mobile Apps. We also offer inexpensive CME/CE, so our content can be used to attain education credits while you study PA-Hospital Medicine.