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1. Disorders of
water and electrolyte
metabolism
Yu-Hong Jia, Ph.D
Pathophysiological department
Dalian medical university
2. • Water is an important component of
human body.
• Water and dissolved particles (solutes) in
it form into body fluid.
• body fluid is the place in which the
metabolism of our body is taken place
• Homeostasis of water and electrolyte in
the body fluid is very important to normal
cell function.
3. • Electrolyte-Compound that when dissolved
in water or another solvent, forms or
dissociates into ions (electrically charged
particles)
– Cations – positively charged
• Na+, K+ , Ca2+, H+
– Anions – negatively charged
• Cl-, HCO3
- , PO4 3-
• Non-electrolytes - Uncharged
• Proteins, urea, glucose, O2, CO2
Solutes – dissolved particles
4. Disorders of water and electrolyte
metabolism
• The consequence of disease
i.e. vomit and diarrhea→ dehydration &
hyponatremia
• Concomitant pathological alteration of
disease
i.e. hypertension + hypokalemia→hint? Primary
increase of ADS (adrenal cortical tumor)
• Danger threaten to life
Be familiar with and grasp the pathogenesis and changing rule of
water and electrolyte disturbance is important for clinical work.
5. • Water disturbance
– ↑water volume
– ↓water volume
i.e. edema
i.e. dehydration
• Electrolyte disturbance
– disturbance of Na+, K+, Ca2+, Mg2+
6. Ⅰ . Body fluid and electrolyte
balance
• Body fluids are composed of
– Water
– Dissolved particles
• Electrolyte
• Non-electrolyte
• Its volume, distribution , composition and
omsmolality is essential to normal cell
metabolism and normal organ function.
7. 1. Body fluid volume
• The total body fluid, or total body water, in a
adult man averages approximately 60% of
his body weight.
– i.e. 60kg body weight
total body fluid is about 36 kg or 36 liter
• Total body fluid can vary with age and sex.
9. Why women have less water than
men if they are the same weight?
The water content of adipose (fat) tissue is
less than that of muscle, while women
have more adipose tissue at the effect of
feminine hormone.
10. •Fluid compartment
are seperated by
membranes that are
freely permeable to
water.
•Movement of fluids
due to hydrostatic
pressure and osmotic
pressure
2. Body fluid distribution
• Body fluids are distributed in
two distinct area:
– intracellular fluid (ICF)
40% body weight
– Extracellular fluid (ECF)
20% body weight
• Interstitial fluid -15% body weight
• Plasma -5% body weight
11.
12. Transcellular fluid
—is a small compartment that represents all those body
fluids which are formed by the secretion of epithelialcell.
—is contained within epithelial lined spaces.
—includes cerebrospinal, pleural, pericardial, peritoneal,
intraocular, synovial and gastrointestinal fluids.
17. 3. Body fluid composition
Cation Anion
Intracellular fluid K+ Mg2+
PO43-
Extracellular fluid Na+
Cl- HCO3-
•ICF and ECF are different in ionic composition. ?
•Plasma and interstitial fluid are identical in ionic composition.
the difference between plasma and interstitial fluid is protein
content. Plasma contains a large amount of protein, while the
interstitial fluid contains less.
?
18. • Answer to question 1
– cell membrane is semipermeable, only water
and small, noncharged molecules can move
freely between interstitial and intracellular
compartment. Ion can not cross easily.
– All kinds of ionic pump or channel on cell
membrane determine the uneven distribution.
• Answer to question 2
– Blood capillary wall is permeable to most
molecules, including water and electrolytes,
except for macromolecule, i.e. protein.
19.
20. 4. Body fluid osmolality
• Osmosis
– movement of water or solvent across a membrane from a
less concentrated solution to a more concentrated solution
• Osmotic pressue
– Pull that draws solvent through the membrane to the more
concentrated side (or side with solute ).
– Determined by the number of particles instead of themass
of the solute in the solution.
– Can be divided in two types:
• Crystal osmotic pressure: formed by a lot of small molecular
weight materials, such as electrolyte, Glucose, BUN and so on.
• Colloid osmotic pressure: formed by large molecular weight
materials such as proteins
21. Figure 7-2
Osmosis When a bottle
bottomed with a
semi-permeable
membrane is filled
with 3% salt
solution and put
into a glass of
water, the water in
the glass will move
into the bottle, this
phenomenon is call
osmosis. Osmosis
make the salt
solution rising and
solution stops rising
when weight of
column equals
osmotic pressure.
22. • Osmole
– Measure of solution’s ability to create osmotic pressure
& thus affect movement of water
– Proportional to the number of osmotic particlesformed
in solution
– 1 mole of nonionizable substance= 1 osmole.
• 1mole of glucose forms a 1 osmolar solution in 1L water
• 1mole of NaCl forms a 2 osmolar solution in 1L water
• 1mole of CaCl2 forms a 3 osmolar solution in 1L water
• Osmolality
– When the concentration of a solution is expressed in
osmoles per kilogram of water, the osmolar
concentration of a solution is referred to as its
osmolality.
– 1 osmoles/kg H2O=1 osmoles/L = 1000 milliosmoles/L=
1000 mOSM =1000mmol/L
23. • In normal condition, the osmolality of plasma
= interstitial fluid = intracellular fluid = 280-
310 mOsm/ kg or 280-310 mmol/L
• The osmolality is determined mainly by:
– in ECF: Na+ and Cl- (80%)
• In clinical practice, serum osmolality can be estimated
by doubling serum sodium
– in ICF: K+ (50%)
Because water can move freely through
cell membrane and blood capillary wall,
so there is no osmotic disequilibrium
among different fluid compartment
24. hypotonic isotonic hypertonic
Particle concentration
compared with intracellular
fluid
fewer same more
Osmolality (mmol/L) <280 280-310 >310
Representative solution 0.45% NaCl
Distilled water
0.9% NaCl
5% glucose
3% NaCl
20% glucose
Response of cell placed in
solution
Swell & burst no alteration wrinkle or shrivel
26. •In tissues with high water permiability (such as the kidney proximal tubule),
water transport occurs at a much greater rate than would be expected across a
pure lipid bilayer.
•This transport is in many cases sensitive to mercuric ions and ADH.
•Suggest the existence of specialized water channels in cell membrane.
transport
Simple diffusion
Water
Interstitial fluid
cell
Water
Intracellular fluid
Water channel
Method of water transport?
27. • The first water channel protein, CHIP28 ( later called aquporin-
CHIP) was purified by Agre and his colleagues from human
erythrocytes in the late 1980s and its cDNA sequence was reported
in 1991.
• The Xenopus oocytes introduced with CHIP28 cDNA will swell
rapidly and burst in five minutes in hypotonic solution. While the
control Xenopus oocytes without aquaporin will be intact.
Aquaporin discovery
28. Aquaporins,AQPs
Peter Agre Roderick MacKinnon
•Aquaporins are a family of small, hydrophobic proteins forming water
selective channels.
•It located in the animal, plant and microorganism.
• Up to now, 11 mammalian AQPs (AQP0-AQP10) have been identified.
Water Channels
2003 Chemistry Nobel Prize
29. Ⅱ . Mechanism for regulating
body fluid and electrolyte
balance
1. The sensation of thirst
2. Antidiuretic hormone
3. Aldosterone
4. The natriuretic peptide family
5. The guanylin family
30. THIRST
• Conscious desire for water
• Major factor that determines fluid intake
• Initiated by the osmoreceptors in
hypothalamus that are stimulated by increase
in osmotic pressure of body fluids
• Also stimulated by a decrease in the blood
pressue through the receptor of baroreceptor.
1. The sensation of thirst
31. Osmoreceptors stimulate AVP secretion and thirst
The vascular organ of the lamina terminalis (OVLT) contains
osmoreceptive neurons – also the subfornical organ (SFO) and the
median preoptic n. (MnPO)
These cells project to the
paraventricular nuclei (PVN)
and supraoptic nuclei (SON)
to produce AVP secretion
32. The regulation of thirsty reaction
The stimulus sensed by osmoreceptor:
•Not a change in the extracellular fluid osmolality per se
•But a change in osmoreceptor neuron size or in the some intracellular
substance.
33. Thirst is inhibited
by decreased
plasma osmolality
(OVLT receptors)
and by increased
blood pressure
(hypervolemia)
Thirst is triggered by increased plasma osmolality (OVLT receptors) ,
decreased plasma volume, and increased plasma AngⅡ which is caused
by decreased plasam volume.(angiotensin II in SFO).
Thirst precisely regulate the volume and osmolality of ECF
36. 2. Antidiuretic hormone(ADH)
• Also called arginine
vasopressin (AVP).
• ADH is produced in
neuron cell bodies
in supraoptic and
paraventricular
nuclei of the
Hypothalamus, and
stored in posterior
pituitary.
• Physiological
function
– Promote the
reabsorption of
water in the
collecting duct.
• Mechanism?
37. The signal pathway following V2
receptor stimulation by ADH
AC: adenylate
cyclase; BLM:
basolateral
membrane; AM:
apical membrane;
V2: vasopressin
receptor; PKA:
protein kinase A
tubule
38. ADH feedback regulation mechanism
Stimulus for secretion of ADH:
●An increase as small as 2% in
osmolality of ECF
● Decrease of arterial pressure
● Decrease of blood volume
● angiotenⅡ
● Emotion stress and pain
39. BP/Blood
volume
+
Stretch receptor
+
Plasma osmotic
pressure
+
-
Osmoreceptor
-+
ADH released?
ADH is more sensitive to the change of osmotic pressure. 1-2%
change of osmotic pressure will change the production ofADH.
At first, when blood volume is not markedly decrease,ADH will not
be increased.
When blood volume is decreased >10%, ADH will be increasedAt
this time, the decrease of blood volume may be life-threatening.
maintenance of body fluid volume has priority over
maintenance of body fluid osmolality.
40. 3. Aldosterone
• Hormone secreted
from the zona
glomerulosa cells of
adrenal cortex
• Stimulates kidneys
– Retain sodium
• Retain water
– Secrete potassium
43. 4. The natriuretic peptide family
• Four peptides of this family have been identified, including:
– Atrial natriuretic peptide (ANP)
– Brain natriuretic peptide (BNP)
– C-type natriuretic peptide (CNP)
– Urodilatin
• release
• Function:
– Diuretic and natriuretic actions
• Mechanism of diuresis and natriuresis
– Three natriuretic peptide receptors termed NPR1, NPR2, and
NPR3 (or NPR-A, NPR-B and NPR-C)
– NPR-A/B are membrane-bound, guanylyl cyclase-coupled
recepteors, and mediate ANP functional effects
– NPR-C lacks guanylyl cyclase domain and acts to clear circulating
natriuretic peptide.
44. Atrial Natriuretic Peptide: Release
•Acute ANP release from cardiac atria
● Atrial distension
● Acute ECF volume expansion
● Saline infusion
● Delivery at the end of pregnancy
● Congestive Heart Failure
•Chronic Increase in ANP Synthesis
● Atrial and Ventricular hypertrophy/stretch
45. Atrial Natriuretic Peptide (ANP)
(causes afferent arterial vasodilation
and relaxes mesangial cells)
(inhibits sympathetic output
from cardiovascular center)
46. NPR-A/B Mediates ANP Functional Effects
NPR-C is Clearance Mechanism
Action of atrial natriuretic peptide at target cells
Levin et al., NEJM (1998) 339:321-328
PDE:
phosphodiesterase
47. 5. The guanylin family
• Types and distribution
– Include guanylin, uroguanylin, lymphoguanylin and exogenous
peptide toxin produced by enteric bacteria
– Guanylin, uroguanylin - highly expressed in gastrointestinal tract
– Lymphoguanylin – kidney, myocardium and lymphoid-immune
system
• Function
– In gastrointestinal tract, stimulate epithelial secretion of Cl- and
HCO-, causing enhanced secretion of fluid and electrolyte into
the intestinal lumen.
– in kidney, increase excretion of Na+, Cl-, K+ and water.
• Mechanism of above functions
– These peptides bind to and activate cell-surface receptors that
have intrinsic guanylate cyclase (GC) activity.
48. An endocrine axis involving uroguanylin released from the GI tract
into the circulation may link the digestive system with the kidney as
one means of influencing body sodium balance
↑RAAS ↑Uroguanylin
released from GI
Sodium oral
intake
Renal excretion of
Sodium
Sodium balance
Increased
decreased
- +
49. • Guanylin binding to
the extracellular side
of the receptor
causes activation of
guanylyl cyclase at
the intracellular side
of the receptor and
further synthesis of
cGMP in intestinal
epithelial cells, which
further leads to
biological effect.
51. Water Steady State
• Amount Intake = Amount Eliminated
To eliminate waste produced by
metabolism, at least 500ml of
urine must be excreted everyday.
disorders
52. Sodium is the primary cation in the
extracellular fluid→ sodium content
determine the osmolality in ECF → while
osmolality gradient across cell membrane
is the driving force of water movement →
so disturbance of sodium is always
accompanied with water disturbance.
53.
54. • Sodium and water disturbances often
occur at the same time and will be
discussed together in this chapter.
55. Classification of disorders of water and sodium metabolism
ECF volume
Hypervolemia
Normovolemia
Hypovolemia
Hypovolemic
hyponatremia
(Hypotonic
dehydration)
Isotonic dehydration
Hypovolemic
hypernatremia
(Hypertonic dehydration)
Normal
Hypervolemic
hyponatremia
(Water intoxication)
Edema
Dehydration: an excessive loss of body fluid.
Serum sodium
concentration
Normovolemic
hyponatremia
(SIADH, Rest osmostat)
Normovolemic
hypernatremia (Upward
resetting of
hypothalamus osmolar
set-point)
Hypervolemic
hypernatremia
(Sodium intoxication)
Hyponatremia
(<130mmol/L)
Disorders of water
metabolism with
normal serum sodium
concentration
(130-150mmol/L)
Hypernatremia
(>150mmol/L)
56. 1. Hypovolemic hypernatremia
Hypertonic dehydration
Concept:
The dehydration in which the water loss is in
excess of salt loss and the remaining ECF of the
body is hypertonic (serum Na+ >150mmol/L,
plasma osmotic pressure> 310mmol/L) is termed
of hypertonic dehydration.
Characteristics:
—Loss of water morethan sodium
—Serum Na+ >150mmol/L
—Plasma osmotic pressure> 310mmol/L
57. Etiology and pathogenesis
•Via gastrointestinal tract
•Via skin
•Via lung
•Via kidney
i.e. diarrhea and vomitting
i.e. ↑environmental and body temperature
i.e. diabetes insipidus, Osmotic diuresis
• Causes of hypertonic dehydration:
water loss is more than sodium loss
(1).↓ Water intake
•Environmental water deficit, i.e. desert
•Difficulty in drinking, i.e. esophageal tumor, coma
•Impaired thirst, i.e. CNS disease
(2).↑ Water loss
58. Diabetes Insipidus
Central diabetes insipidus is characterized by
decreased secretion of antidiuretic hormone (ADH)
that results in polyuria and polydipsia by diminishing
the patient's ability to concentrate urine.
Nephrogenic diabetes insipidus is characterized by a
decrease in the ability to concentrate urine due to a
resistance to ADH action in the kidney.
60. Alterations of metabolism and function
1. hyperosmolality of ECF →stimulate thirst mechanism →thirst
↑Ingestion ↑ECF volume
of water ↓ECF osmolality
2. Hyperosmolality of ECF → stimulate secretion ofADH
→↑renal tubular reabsorption of water → decrease of urinary
volume & increase of urinaryconcentration ↑ECF volume
ICF
Interstitial
fluid
plasma
The relative volume
change of ICF,
interstitial fluid and
plasma.
↓ECF osmolality
3. Hyperosmolality of ECF →water shift from intracellular to
extracellular compartment →cell dehydr↑aEtioCnFavnodlusmhreinkage
↓ECF osmolality
61. Alterations of metabolism and function
(continued)
4. Early stage, change of blood volume not obvious→ADS
not increase→Na+ reabsorption not increase
2
↑ADH →H O reabsorption increase
↑Urinary
sodium
Late state, decrease of blood volume →increase of ADS
→ Na+ reabsorption increase →↓urinary sodium
5.Brain cell dehydration→ CNS dyfunction, such as
twitching, somnolence, coma
6.hypovolemia→ reduced blood pressure, elevation in
body temperature
62. Principles of Therapy:
Treating the primarydisease
Supplying 5%-10% Glucose
Adding a small amount of NaClsolution
Adding K+ properly
63. 2. Hypovolemic hyponatremia
Hypotonic dehydration
Concept:
The dehydration in which the salt loss is in excess of water
loss and the remaining ECF of the body is hypotonic (Serum
Na+ <130mmol/L, Plasma osmotic pressure< 280mmol/L) is
termed of hypertonic dehydration.
Characteristics:
—Loss of sodium more than water
—Serum Na+ <130mmol/L
—Plasma osmotic pressure< 280mmol/L
64. •Via gastrointestinal tract
•Via skin
•Body fluid accumulation in the third space
Etiology and pathogenesis
• Hypotonic dehydration almost all appear after inappropriate
therapy, that is after excessive loss of water and salt, only
water but not salt is given.
1. Loss of sodium via kidney
• inappropriate long-term use of diuretics
•Adrenocortical insufficiency
•Renal disease
•Renal tubular acidosis
2. Loss of sodium via extra-kidney
furosemide→inhibit Na+ reabsorption
by Henle’s loop ascending branch
→ ↓ADS → ↓renal Na+ reabsorption
Chronic interstitial nephritis → impairment of medullary interstitium
and dysfunction of Henle’s loop →↑urinary Na+ excretion
A decrease in H+ excretion in the collecting duct causes the
dysfunction of H+-Na+ exchange → ↑urinary sodium excretion
Vomitting, diarrhea
Serious perspiration, burn
peritonitis→ascites
65. Alterations of metabolism and function
The relative volume
change of ICF,
interstitial fluid and
plasma.
ICF
Interstitial
fluid
plasma
1. hypoospmolality of ECF →inhibit thirst mechanism →no thirst
2. Early stage, hypoosmolality of ECF → inhibit secretion of ADH
→↓renal tubular reabsorption of water → polyuria and & urinary
dilution
late stage, blood volume seriouly decreased →↑ADH → oliguria
3.Hypoosmolality of ECF →water shift from extracellular to
intracellular compartment → ECF volume further decrease
Decrease skin turgor,
postural hypotension,
tachycardia, shock
66. Alterations of metabolism and function
(continued)
4.Water movement into cells → Brain cell swelling→ CNS
dyfunction, such as nausea, vomiting, twitching, confusion,
lethargy, stupor and coma.
5. If sodium loss via kidney→↑urinary sodium
If sodium lossvia extra-kidney, decrease of blood volume
→increase of ADS → Na+ reabsorption increase
→↓urinary sodium
68. 3. Isotonic dehydration
Concept:
• The dehydration in which the salt loss is identical to water
loss and the remaining ECF of the body has the normal
osmolality is termed of isotonic dehydration
Characteristics:
—Loss of water identicle tosodium
—Serum Na+ : 130-150mmol/L
—Plasma osmotic pressure: 280-310mmol/L
69. Causes:
Vomiting, diarrhea, hemorrhage and loss of
body fluid through burned area.
Influences:
Reduced ECF volume initiates a series of
adaptive response, including thirst, ADH
and ADS release.
71. 4. Hypervolemic hyponatremia
Concept:
• A hyponatremia with increased extracellular fluid volume,
always associated with increased total body sodium and
total body water, but the increase of water is greater than
that of sodium.
• When hypotonic ECF is excessively increased, this
disorder is also termed water intoxication.
Characteristics:
—Serum Na+ < 130mmol/L
—Plasma osmotic pressure < 280mmol/L
72. Etiology and pathogenesis
•Tap water enema
•Psychotic drinking
•Excessive intravenous infusion of hypotonic solution
(2). Decreased Water loss
Over retention of hypotonic fluid in the body
(1). Excessive water intake
which exceed the
ability of renal
excretion of water
•Acute renal failure
•Over secretion of ADH caused by phobia, pain, hemorrhage, shock
and trauma
In general, water intoxication mostly occurred in patient with acute
renal failure and infused inappropriately at the same time.
73. Alterations of metabolism and function
• Hypoosmolality of ECF
water movement into cells cell swelling
Signs and symptoms
of brain cell swelling
• Hypervolemia of ECF
Elevated blood pressure,
blood dilution
74. 5. normovolemic hyponatremia
Concept:
• A hyponatremia with almost normal extracellular fluid
volume.
Characteristics:
—Serum Na+ < 130mmol/L
—Plasma osmotic pressure < 280mmol/L
75. •Malignant tumors,
•Cerebral disorders,
i.e. pancreatic, duodenal and prostatic carcinoma,
leukemia
i.e. infection, trauma
•Pulmonary diseases i.e. tuberculosis, pneumonia, lung abscesses
Etiology and pathogenesis
1. syndrome of inapproriate ADH secrection (SIADH)
2. reset osmostat syndrome.
76. SIADH
• Although this disorder is called normovolemic, in
fact the ECF volume is slightly increased.
SIADH→↑ADH →↑renal reabsorption of water
diluted serum sodium
↑GFR
↓Reabsorption
of sodium at
proximal tubule
↑ ANP
↓ADS
natriuresis
↑Water
excretion
slight ECF volume expansion
-
77. Alterations of metabolism and function
hyponatremia→ water shifting into cells→
brain cell edema→ CNS dysfunction
78. 6. hypervolemic hyperatremia
Concept:
Is a disorder in which extracellular fluid volume expansion
and hypernatremia coexist.
causes:
—Iatrogenically over infusion of salt solusion, i.e. infusion of
hypertonic salt solution to correct the hypotonic dehydration
—Primary sodium retention, i.e. primary hyperaldosteronism
Alterations of metabolism and function:
• hyperosmolality of ECF→ thirst, ↑ADH
• hypervolemia→ circulating overload, hypertension, edema
79. 7. normovolemic hypernatremia
upward resetting of
osmolar set-point
Osmoreceptor insensitive to
osmotic stimulus
Only osmotic pressure is obviously
higher than normal level
Thirst, ADH secretion
Baroreceptor,
stretchreceptor
Change of blood
volume or pressure
Characteristics:
• serum sodium concentration is increased, while extracellular fluid
volume is normal.
Etiology and pathogenesis:
Hypothalamus disease
abnormal
normal
Normal: >150mmol/L
Abnormal: >160mmol/L
150-160mmol/L
[Na+]
hypernatremia normovolemia
80.
81. Effects of hypernatremia on the brain. Brain shrinkage within
minutes of development of hypertonicity.Rapid adaptation in
few hrs. Rapid correction results in cerebral edema
82. Effects of hyponatremia on the brain and adaptive responses.
Brain swelling occurs in minutes of developing hypotonicity,
Partial restoration in hrs, normalization of brain vol in days.
Overly aggressive correction of Na can lead to irreversible brain
damage
83. Application Problem 1
•Michael has recently started working
outdoors in the hot weather to earn
money for his tuition. After a few
days he experienced headaches, low
blood pressure and a rapid heart rate.
His blood sodium was down to 125
meq/L. The normal is 144 meq/L.
How do you explain this?
84. Answer to Problem 1
• Michael lost sodium by perspiration.
The low sodium in his blood allowed
fluid to move into cells by osmosis.
Lack of fluid lowered his blood
pressure to give him a headache. The
increased heart rate was his bodies
way of trying to increase blood
pressure.
85. MILLIEQUIVALENT (mEq)
• Unit of measure for an electrolyte
• Describes electrolyte’s ability to
combine & form other compounds
• Equivalent weight is amount of one
electrolyte that will react with a given
amount of hydrogen
• 1 mEq of any cation will react with 1
mEq of an anion
87. Osmotic Concentration
• Proportional to the number of osmotic
particles formed: Osm/L = moles x n (n, # of
particles in solution)
• Assuming complete dissociation:
– 1mole of NaCl forms a 2 osmolar solution in 1L
– 1mole of CaCl2 forms a 3 osmolar solution in 1L
• Physiological concentrations:
– milliOsmolar units most appropriate
– 1 mOSM = 10-3 osmoles/L
e.g. 1 M NaCl = 2 M Glu in Osm/L
88. Classification of disorders of water and sodium metabolism
ECF volume
Hypervolemia
Normovolemia
Hypovolemia
Hypotonic dehydration
Isotonic dehydration
Hypertonic dehydration
Normal
Water
intoxication
Edema
Dehydration: an excessive loss of body fluid.
Serum sodium
concentration
SIADH
Rest osmostat
Upward resetting of
hypothalamus
osmolar set-point
Sodium
intoxication
Hyponatremia
(<130mmol/L)
Disorders of water &
sodium metabolism
with normal serum
sodium concentration
(130-150mmol/L)
Hypernatremia
(>150mmol/L)