CHEMICAL PATHOLOGY LECTURE on water sodium and the relationship to electrolyte balance

1. Water and
Electrolytes
Balance
MBCHB 18-11-21
T.Nyamayaro
Chemical Pathology

2. Outline
• Fluid Compartments
• Composition of body fluids
• Osmolality and Fluid Balance
• Regulation of hydration status
• Water depletion and excess.
• Hyponatraemia and hyponatraemia.
• Hypokalaemia and hyperkalaemia

3. Ref.
1. Textbook of Clinical Chemistry – N.W.Tietz
2.Clinical Chemistry – -Fourth Edition William J Marshall
3. Fluid, Electroytes and Acid Base Disorders - Spiringer
4. Clinical Chemistry in Diagnosis and Treatment- Sixth
Edition –Zilva , Pannall and Mayne
5. Dr. B Sedumedi – SMU 4th Chemical Pathology Notes

4. WATER
• Is 50-70% of body wt
• Varies with age, higher in infants than in adults
• In Males 60%, Females 50 %, Elderly 45%
⮚ Difference due to increase in additional fat
• Varies with Country, Race, Economic status, etc
Content is greatest in Brain Tissue (about 90%)
- least in Adipose Tissue (about 10%)
⮚ 70 kg ‘male' contains about 40 liters of water

6. FUNCTIONS OF WATER
• CARRIES nutrients, waste products, enzymes, RBCs etc
• REGULATION of blood VOLUME, electrolyte and ion balance
• MAINTAINS the STRUCTURE of large molecules ( e.g.
proteins )
• Participates in CHEMICAL REACTIONS
• SERVES as SOLVENT for nutrients
• Regulates and maintains body TEMPERATURE
• Tissue LUBRICANT and cushion for JOINTS
• SHOCK ABSORBER (eyes, spinal cord, amniotic sac)

7. BODY FLUID COMPARTMENTS
• WATER occupies TWO MAJOR compartments:
1. Intracellular Fluid (ICF):
✔ In cells app. 67% (2/3) total body fluid
2. Extracelluar Fluid (ECF):
✔ Out side of cells app. 33% (1/3) of the total
body fluid

8. Extracelluar Fluid (ECF):
• Subdivided into three compartments:
✔ Intravascular - blood (plasma): found within vascular system.
✔ Interstitial : surrounding the cell and includes lymph.
✔ Transcellular : contained within specialized
cavities of the body (includes CSF, pleural, peritoneal and synovial fluids).

9. Intracellular Fluid (ICF):
Extracellular Fluid (ECF
67% (2/3) total body fluid
33% (1/3) of the total body fluid
Intravascular
(plasma):
Interstitial

10. (TOTAL BODY WATER)

13. Homeostasis maintained by:
• Ion transport
• Water movement
• Kidney function

14. Movement of fluid and solutes between compartments
• Simple diffusion
• Active transport
• Filtration
• Facilitated Diffusion
• Co-transporter
⮚ Note ; “ Where sodium goes, water follows.”

15. SIMPLE DIFFUSION
Movement depends on two semipermeable membranes:
a. Cellular membrane: allows distribution between ICF & ECF –
determined by ECF osmolality/tonicity
Osmosis
b. Capillary membrane : allows distribution between plasma & ISF -
determined by oncotic and hydrostatic pressures (Starlings’ forces)

16. Active Transport
The Na/K pump maintains electrolyte gradient balance between the
cytoplasm and the ECF.

17. Facilitated Diffusion
Glucose molecules use facilitated diffusion to move down a concentration
gradient through the carrier protein channels in the membrane

18. Cotransporter
The sodium-glucose cotransporter-2 (SGLT2) mechanism in the proximal
tubule

19. BODY FLUIDS are:
• Electrically neutral
• Osmotically maintained
⮚ Contain specific number of particles per volume
of fluid

22. WATER BALANCE
• WATER consumed (in food & drink & generated by metabolism)
equals the water excreted
• Total body water remains the same from day to day
• Kidneys essential in regulation of both volume and
composition

23. Average daily water Intake & Output of a Healthy adult
Intake ml Output ml
Water drunk 1500 Urine volume 1500
Water in food 750 Insensible perspiration 400
Metabolism 250 Lungs 450
Faeces 150
Total intake 2500 Total output 2500

24. Route of water loss depends on
✔ Temperature
✔ Relative humidity
✔ Physical exercise
⮚ NOTE minimum urine output of 500 ml is required
For the excretion of waste products
✔ If concentrating power of kidney is diminished through disease
OR
✔ if renal load of metabolic waste products is increased
⮚ Minimum VOLUME of urine required for excretion of waste
products will be higher

25. OSMOLALITY (RR 280-290)
• Measure of the number of dissolved particles per kg of
water
• A measure of the osmotic pressure exerted by a
solution
Calculated osmolality
• Osm(calc) = 1.86 (Na+ + K+ ) + Glu + Urea + 9
Or 2(Na +K) +Gluc + Urea

26. ECF and ICF Osmolality
• In the body all cells are freely permeable to water.
(with the exception of the collecting ducts of the renal medulla)
• Thus, an osmotic gradient between a cell and its environment
CANNOT develop
• ECF osmolality is always equal to ICF osmolality
(Normal 280-290 mosmol/kg).

27. ECF and ICF Osmolality (cont.)
• Distribution of water depends on concentration of particles
in the compartments
• Small M.W. particles exert a greater osmotic effect, as
compared to bigger particles.
• Plasma proteins, despite MASSIVE sizes, exert a relatively
insignificant osmotic effect
⮚ Osmolalities of ECF and ICF are equal, BUT solutes
responsible for them are very different

28. Contributors to ECF & ICF Osmolality
ECF osmolality-
• Na+ (cation) with Cl- & HCO3- (anions)
ICF osmolality
• K+ & Mg2+ (as cations), and organic PO4, including ATP,
creatine phosphate & glycolytic intermediates (as anions)
NOTE
• ECF[Na+] => 140mmoL
• ICF[Na+] => 10mmol).

29. Water movement and Osmolality
• Any increase in ECF [Na+] results in water moving from cells into the ECF =>
leads to intracellular DEHYDRATION.
• If ECF [Na+] FALLS water passes into cells leading to cell SWELLING
NOTE : DETERMINANT of water movement is ECF Na+ concentration NOT
Total Na+ content

30. Take home message !!!!!!
⮚ Content of Na+ determines ECF volume
⮚ Concentration of Na+ in the ECF reflects ICF volume

31. The Brain and Osmolality
• Changes in cell volume important in the BRAIN
⮚ Cerebral dehydration causes the brain to pull away from
the meninges, rupturing meningeal vessels
⮚ Cerebral swelling (oedema) causes compression of the
brain against the rigid skull
• In either case, individuals exhibit neurological symptoms;
=> from - Altered behaviour or irritability,
- Impaired level of consciousness,
to - convulsions and coma.

32. Plasma Osmolality & Osmolal Gap
• Osmolality can be measured or calculated (osmolarity)
⮚ Measured = total osmolality (sum of the osmotic effects
exerted by all ions & molecules present in solution)

33. Plasma Osmolality & Osmolal Gap (cont.)
Calculated plasma osmolarity = rough estimate mmol/L
= 2 x [Na+ + K+] + [urea] + [glucose]
⮚ The factor 2 is to allow for the major anions binding the Na/k
• Note that determined Osmolality includes calculated osmolarity + concentrations of
other solutes present in plasma.
• Therefore Osmolality cannot be less than osmolarity
If osmolarity > osmolality suspect:
✔ laboratory error
✔ calculation error

34. Plasma Osmolality & Osmolal Gap
Osmolal gap (measured – calculated) - should agree within 10
mmol/kg.
High osmolal gap - clinically significant => presence of non electrolyte
solutes other than glucose, urea
Causes
✔ Alcohols – methanol, ethanol, ethylene glycol
✔ Sugars – mannitol, sorbitol
✔ Ketoacidosis, lactic acidosis
✔ Hyperlipopoteinaemias
✔ Hyperproteinaemia

35. Urine osmolarity
Urine osmolarity = 2 x (urine Na) + Urine K + (urinary urea nitrogen/2.8) +
(urine glucose/18)
(RR urine osmolarity of a 24-hour urine 500 to 800 mOsm/kg

36. Tonicity (Effective Osmolality)
• Small M.W, substances (e.g.urea alcohol,) able to diffuse freely
across cell membranes
• DO NOT exert an osmotic gradient & therefore DO NOT induce fluid
shifts
⮚ e.g, In Renal failure (urea) and in a drunken stupor, (ethanol), can
increase plasma osmolality by over 50 mosmol/kg, without activating
the osmostat.

37. WATER BALANCE
• Is maintained primarily by
✓ Sensation of thirst (intake)
✓ Anti-Diuretic Hormone (ADH)
• Control of ADH (vasopressin) is mainly through
✓ Osmolality
✓ Blood pressure
• Atrial Natriuretic Peptide (ANP) and angiotensin II
⮚ Drugs including nicotine (stimulates) & ethanol (inhibits) ADH
release

38. MECHANISM SOURCE STIMULUS EFFECT
1. GFR Kidney Normal Renal
Function
Permits Na+ &
water
excretion
2. Aldosterone Adrenals ↓ Renal perfusion Renal Na+ &
Water
retention
3. ADH (Anti-
Diuretic
Hormone)
Hypothalamus ↑ ECF tonicity
↓↓↓ blood volume
Pure water
retention
4. ANP (Atrial
Natriuretic
Peptide)
cardiac atria ↑ Blood volume Renal Na+ &
water
excretion
Regulation of the Body’s Hydration Status

39. Factors influencing ADH secretion
1. Osmoreceptors - in hypothalamus, very sensitive
respond to 1-2% 🡹🡹 in ECF osmolality (tonicity) by 🡹🡹
ADH production
1. Blood volume baroreceptors, in the right atrium and
carotid arteries responds to 10% change in volume.
⮚ Can override the effect of ECF tonicity on ADH
secretion e.g., in Addison's disease, when the
plasma is hypo-osmolal

40. NOTE
• Anything that stimulates ADH also stimulates thirst
⮚ However thresh hold for Thirst is higher than thresh hold
for ADH secretion
⮚Thus osmolality is controlled largely by effects of ADH
☞ The osmotic concentrations (osmolalities) of ECF & ICF
compartments are always Equal (isotonic).
☞ Any change in solute content of a compartment brings in
water which restores isotonicity

41. DISORDERS OF SODIUM
AND
WATER BALANCE

42. Principal abnormalities of water balance
• Dehydration/Volume depletion
• Hypotonic hydration/Oedema

43. DEHYDRATION
and VOLUME DEPLETION

44. Dehydration (cont.)
• TWO CATEGORIES
✔ Water loss only (hypotonic fluid loss)
and
✔ Accompanied by an equivalent loss of Na+ (isotonic fluid
loss)
Note : These are two extremes real clinical scenarios
fall somewhere in between.

46. DEHYDRATION (Volume Depletion)
Causes
1. Reduced intake
✔ Water unavailable
✔ Patient unconscious
✔ Severe dysphagia (difficulty in swallowing)

47. 2. Excessive loss by one or more routes
a. Lungs
✔ Hyperventilation or assisted ventilation with unhumidified air
b. Urine
✔ Diabetes insipidus (DI)
✔ Nephritis
✔ Osmotic diuresis (eg. Diabetes mellitus)
c. Intestinal tract
✔ Diarrhoea
✔ Vomiting
d. Skin - severe sweat
✔ Hot climates, exercise
✔ Severe fever
3. Combination 🡹 intake & excessive loss - Cessation of water
intake with on going obligatory water loss eg.in infants, elderly or
unconscious patients.

48. HYPOTONIC FLUID LOSS (Dehydration)
Biochemical & Clinical features
⮚ H2O lost in excess of Na+ from the ECF
✔ ECF [Na+] rises, moves H2O from the ICF
✔ Signs of cerebral dehydration (confusion, etc) may be present
✔ 🡹 Plasma tonicity ('effective' osmolality) rapidly evokes an immediate
ADH and thirst response
✔ Urine is maximally concentrated, with urine osmolality
approaching 1000 mosmol/kg (except,, when the cause of the
water loss is diabetes insipidus)

49. Hypotonic Fluid Loss (Dehydration)
Biochemical & Clinical features (cont.)
• Movement of H2O from ICF to ECF minimizes the depletion
in bld vol, signs of circulatory collapse (tachycardia, low BP,
oliguria) are less pronounced (occur later)
• When bld vol has become sufficiently depleted, renal
underperfusion evokes renin release, which, via the
angiotensin pathway, stimulates aldosterone secretion.

50. Hypotonic Fluid Loss (cont)
Biochemical & Clinical features (cont.)
• Aldosterone promotes Na+ uptake by the distal tubules,
results in extremely low urine [Na+] (<10mmol).
⮚ This differentiates the hypernatraemia due to water
depletion from that due to excess salt intake
⮚ Hypernatraemia due to excess NA+ has , very high urine
[Na+] ( >100mmol ).

53. Management
• Fluids replacement with a low Na+ content
─ Either water by mouth
or
─ If unable to drink, 5% glucose or 0.5N
NaCL intravenously
⮚ Over-rapid correction if the hypernatraemia has been long-
standing, poses a risk of cerebral oedema.

54. ISOTONIC FLUID LOSS
Biochemical & Clinical features (cont.)
• Water lost with an equivalent amount of Na+
• No immediate change in plasma [Na+], hence No movement
of fluid from the ICF
⮚ Cerebral dehydration is NOT a problem.
⮚ All fluid lost comes from the ECF, & circulatory collapse is
more pronounced
⮚ Pts can present with shock, appear pale with tachycardia
and hypotension.

55. Isotonic Fluid Loss (cont.)
Biochemical & Clinical features (cont.)
• GFR may drop rapidly, with a falling urine output, and a
progressive rise in plasma [urea] and [creatinine]
• Signs of haemo-conc. 🡹 [Hb], 🡹 [TP]) may be present (unless,
haemorrhage is the cause of the fluid loss)
• 🡹 in renal perfusion triggers early aldosterone release -
renin/angiotensin mechanism (except in Addisons disease
where lack of aldosterone is the basic problem).

56. Isotonic Fluid Loss (cont.)
Biochemical & Clinical features (cont.)
• As with hypotonic fluid Loss urine is highly conc, with a very
low [Na] (<10mmol/l)
• Since plasma osmolality is unchanged, there is NO osmotic
stimulus for early ADH
• ADH release only once blood volume depletion is severe.

57. ISOTONIC FLUID LOSS management
• Rapid replacement with IV isotonic saline (0.9%nacl) till
urine output is normal.
• No danger of cerebral oedema since infused fluid is isotonic.
• Note Delay in treatment results in ARF
⮚ After restoring ECF volume, identify & treat the underlying
problem (eg stop diuretics, give minerallo-corticoid
replacement for Addisons, etc).

58. HYPOTONIC ISOTONIC
Plasma [Na+] ↑↑ Normal To ↓
Hematocrit Slightly ↑ ↑↑↑
ECF volume ↓ ↓↓↓
Plasma [urea] Normal To ↑ ↑
Urine output ↓↓↓ ↓
Thirst Early Late
Tachycardia &
hypotension
Late Early
Fluid replacement Cautious Rapid
Comparison Between Hypotonic With Isotonic Fluid Loss

59. Clinical features Of ECF depletion
✔ Postural decrease in blood pressure
✔ Increased pulse (trying to maintain cardiac output )
✔ Dry mucus membranes
✔ Soft/sunken eyeballs
✔ Decreased skin turgor
✔ Decreased consciousness
✔ Decreased urine output
✔ Note: pure states of depletion water (without Na+
depletion) uncommon

61. Causes of Isotonic Fluid Loss
• Haemorrhage
• Burns
• GIT loss (diarrhoea, vomiting, fistula)
• Renal loss (diuretics, polyuric recovery phase of acute renal
failure, addisons disease)
• Internal body spaces loss: ileus, ascites, pleural effusion
hematoma, pancreatitis

62. OVERHYDRATION
(WATER OVERLOAD)

63. WATER OVERLOAD
• Sub-divided into
1. Pure water overload
2. Isotonic water overload (water plus an equivalent
amount of Na+).

64. WATER OVERLOAD (cont.)
CAUSES
a. Increased intake – rare kidneys can excrete at least one
litre/hour.
✔ Compulsive water drinking
✔ Hypotonic saline (parenteral)
b. Impaired (decreased) output (excretion)
✔ Renal disease (severe)
✔ Adrenal failure
✔ Inappropriate or ectopic secretion of ADH

66. Causes of Pure Water Overload include:
1. Water intake > 1litre/hour
✔ Mental disorder (psychogenic polydipsia)
✔ Dedicated beer drinkers.
✔ ‘Salt-losing nephritis’ or diuretics that impair tubular salt
reabsorption.
2. Syndrome of Inappropriate ADH (SIADH) secrection, due to the
failure of a low plasma osmolality to suppress ADH secretion

67. SIADH (cont.)
NOTE
• Continued ADH secretion in the presence of decreased
plasma osmolality causes
1. The body to retain water inappropriately
2. Euvolaemic hyponatraemia
3. An inappropriately concentrated urine
⮚ Occurs on normal salt and water intake, and absence of
hepatic, cardiac, thyroid, adrenal, pituitary or renal
dysfunction and other factors known to stimulate ADH
secretion

68. SIADH AETIOLOGY
1. Intracranial pathology (head injury, haemorrhage, meningitis, or brain
tumour) resulting in direct stimulation of hypothalamic ADH
release.
2. Pulmonary pathology (pneumonia, TB, assisted ventilation), where
volume receptors in the pulmonary vascular bed falsely report a message of
vascular depletion to the hypothalamus
1. Ectopic production of ADH by tumours particularly bronchial, -
brain or bronchial, oropharynx, or GI tumours

69. SIADH Aetiology cont.)
3. HEREDITARY - four different types of ADH problems
a. High ADH
b. High basal ADH - 'vasopressin leak‘ => incomplete suppression of ADH
release when osmolality falls.
c. Low setpoint ‘ osmostat‘ reset so that osmolality is still controlled but
at a low setpoint level
d. Active receptor - production of vasopressin is entirely normal but
response to the hormone is abnormal

70. SIADH Aetiology cont.)
4. CERTAIN DRUGS => stimulate vasopressin release or have a
vasopressin-like action on the kidney
e.g antiepileptics, anticonvulsants, antipsychotics
4. TRANSIENT => nausea, pain, stress, from trauma or surgery (hospital
patients) stimulates ADH release.

71. Findings in SIADH
• Pts over-hydrated, but have no oedema - retained water is shared
between the ECF and ICF
• ECF expansion is eventually limited by release of Atrial
Natriuretic Factor (ANF) from cardiac atria, => promotes sodium
excretion
⮚ Major problem => hyponatraemia, leading to cerebral oedema and
consequent depressed level of consciousness

73. Management of SI ADH
• Treatment of the cause e.g. Brain tumor resection
• Restriction of water intake in mild cases
• Furosemide to get negative water balance
⮚ Replace fluid by isotonic or hypertonic saline
• Measure serum sodium every 6 to 12 h.

74. ISOTONIC FLUID OVERLOAD
Major causes
• Administration of excess isotonic fluid, particularly to
patients with impaired renal function.
• Hyperaldosteronism, (the inappropriate secretion of
aldosterone despite an expanded ECF volume
✔ Primary
or
✔ Secondary.

75. Primary Hyperaldosteronism (Conn's Syndrome)
• Secretion of aldosterone by an adrenal adenoma
• Results in ;
✔ Excessive Na+ and water reabsorption with
concomitant loss of K+ and H+.
✔ Hypokalaemic alkalosis, with plasma Na + normal to
slightly increased.

76. Secondary Hyperaldosteronism
• Excessive aldosterone secretion in response to persistent
renin secretion
⮚ No ECF volume depletion , i.e. renin secretion is inappropriate
• Due to
✔ Renin-secreting tumor (rare).
✔ Disturbance in the blood supply to one or both kidneys,
eg. renal artery stenosis

77. Diabetes insipidus (DI)

78. Diabetes insipidus (DI)
• Inadequate secretion or effect of ADH
• Results in the excretion of large volumes of dilute urine
(polyuria)
⮚ Causes the individual to consume large quantities of fluid
(polydipsia)
• Several forms of DI

79. Forms of Diabetes insipidus
• Neurogenic – decreased ADH production
Causes - hypothalamic or pituitary stalk lesion, - idiopathic and inherited
forms
• Nephrogenic – defect in the renal receptor causing decreased response
to ADH
Causes – genetic defects, metabolic abnormalities, drugs, heavy metals,
chronic kidney disease

80. Water Deprivation Test
• Done on patients presenting with polyuria and low urine
osmolality
• For diagnosis of diabetes insipidus
• Done Under medical supervision
• Patients are deprived of water for up to 8 hours
• The following parameters are measured
✔ Body weight
✔ Urine output
✔ Serum and Urine osmolality

81. Water Deprivation Test
• Serial urines are collected, and their osmolalities are
measured
• When urine osmolality plateaus out, (i.e. there is no further
increase in osmolality of sequential urine specimens), ADH is
administered
• Osmolality of urine is noted

82. Water Deprivation Test
Interpretation:
• In Normal and psychogenic polydipsia, urine osmolality rises progressively
during water deprivation until it reaches the high hundreds (700-
800mosmol/kg).
• Plasma [Na+ ] and body weight show negligible change.
• In diabetes insipidus (DI), urine osmolality plateaus out at a much lower
value (eg. 200-300 mosmol/kg), depending on the severity.
• There is a progressive increase of plasma Na+ and loss of body weight, and
patients soon become thirsty and distressed from dehydration.
• If the DI is neurogenic, urine osmolality increases after ADH is given,
whereas in nephrogenic DI, it remains unchanged.

83. Water Deprivation Test
Interpretation:
In normal subjects and psychogenic polydipsia
• Urine osmolality rises progressively during water
deprivation until it reaches the high hundreds (700-
800mosmol/kg).
• Plasma [Na+] and body weight show negligible change

84. Water Deprivation Test (Interpretation cont.)
In diabetes insipidus (DI)
• Urine osmolality plateaus out at a much lower value (eg.
200-300 mosmol/kg), depending on the severity.
• There is a progressive increase of plasma Na+ and loss of
body wt, and pts become thirsty and distressed from
dehydration.

85. Water Deprivation Test (Interpretation cont.)
• If Neurogenic DI , urine osmolality increases after ADH is
given
• In Nephrogenic DI, urine osmolality remains unchanged

86. Water Deprivation Test (Interpretation)
• Primary polydipsia – low plasma osmolality at the start of
the test but will concentrate urine during water
deprivation
• Diabetes insipidus – confirmed by a plasma osmolality of
>300 and a urine osmolality of <300

90. ????????????