WATER METABOLISM

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WATER METABOLISM
Unregulated food social drink Insensible
and obligate loss
Regulated thirst AVP modulated water
output
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THIRST

• Hyperosmolar stimulus
• hypothalamic osmoreceptors
• threshold 1 to 4 above basal
• Hypovolaemic stimulus
• baroreceptors
• threshold 10 - 15
• ? absent in man (inconvenient with postural
  change!)
• Normally inactive as unregulated input is in
  excess

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BASAL
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AVP secretion

• Synthesized in hypothalamic SON and PVN nuclei
• Stored and released from posterior pituitary (gt 1
  week store!)
• Interacts via V2 receptors to insert aquaporin-2
  water channels
• Osmolar threshold within normal range
• High gain (i.e steep curve and high renal
  sensitivity)

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AVP secretion

• Osmotic stimulus high sensitivity
• Hypovolaemic stimulus high threshold (gt10)

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AVP secretion

• Osmotic stimulus high sensitivity
• Hypovolaemic stimulus high threshold (gt10)
• Nausea most powerful known
• Stress e.g. post-operative
• Drugs SIADH

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INTEGRATION OF THIRST AND AVP

• Unregulated water intake supplies water in excess
  of need
• Excess water is excreted
• AVP secretion regulates free water clearance
• AVP maintains osmolality within narrow limits
• This avoids inconvenient thirst and
  water-seeking behaviour
• Thirst kicks-in when deficiency reaches harmful
  levels

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DIFFERENTIAL DIAGNOSIS OF HYPONATRAEMIA
HYPONATRAEMIA
Pseudo- hyponatraemia
YES
Lipaemia / hyperproteinaemia ?
NO
Compensatory hyponatraemia
Hyperglycaemia ?
YES
NO
Volume expanded
Volume depleted
Total body water
Renal loss
Extra-renal loss
No oedema
Oedema
Diuretics Addisons
Vomiting Diarrhoea
SIADH Hypothyroid
Nephrotic Cirrhosis CCF
UNa
gt20
lt10
lt10
gt20
Rx
Normal saline
Fluid restriction
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Causes of hyponatraemia
HYPONATRAEMIA
Pseudo- hyponatraemia
YES
Lipaemia / hyperproteinaemia ?
NO
Compensatory hyponatraemia
Hyperglycaemia ?
YES
NO
Volume expanded
Volume depleted
Total body water
Renal loss
Extra-renal loss
No oedema
Oedema
Diuretics Addisons
Vomiting Diarrhoea
SIADH Hypothyroid
Nephrotic Cirrhosis CCF
UNa
gt20
lt10
lt10
gt20
Rx
Normal saline
Fluid restriction
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Causes of hyponatraemia
HYPONATRAEMIA
Pseudo- hyponatraemia
YES
Lipaemia / hyperproteinaemia ?
NO
Compensatory hyponatraemia
Hyperglycaemia ?
YES
NO
Volume expanded
Volume depleted
Total body water
Renal loss
Extra-renal loss
No oedema
Oedema
Diuretics Addisons
Vomiting Diarrhoea
SIADH Hypothyroid
Nephrotic Cirrhosis CCF
UNa
gt20
lt10
lt10
gt20
Rx
Normal saline
Fluid restriction
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Case 1

• A 58-year old man presented with a history of
  general malaise and a persistant painful cough of
  three months duration
• Serum
• Sodium 116 mmol/L
• Potassium 3.4 mmol/L
• Urea 9.4 mmol/L
• Bilirubin 12 umol/L
• Alk phos 95 U/L
• ALT 23 U/L
• Albumin 20 g/L
• Total protein 120 g/L

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Causes of hyponatraemia
HYPONATRAEMIA
Pseudo- hyponatraemia
YES
Lipaemia / hyperproteinaemia ?
NO
Compensatory hyponatraemia
Hyperglycaemia ?
YES
NO
Volume expanded
Volume depleted
Total body water
Renal loss
Extra-renal loss
No oedema
Oedema
Diuretics Addisons
Vomiting Diarrhoea
SIADH Hypothyroid
Nephrotic Cirrhosis CCF
UNa
gt20
lt10
lt10
gt20
Rx
Normal saline
Fluid restriction
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Case 3

• A 66-year old man was admitted for investigation
  of possible bronchogenic carcinoma
• Serum Ref range
• Sodium 121 mmol/L 133 143
• Potassium 4.1 mmol/L 3.6 4.6
• Urea 4.4 mmol/L 3.0 7.0

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Case 3

• A 66-year old man was admitted for investigation
  of possible bronchogenic carcinoma
• Serum Ref range
• Sodium 121 mmol/L 133 143
• Potassium 4.1 mmol/L 3.6 4.6
• Urea 4.4 mmol/L 3.0 7.0
• Glucose 5.2 mmol/L

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Case 3

• A 66-year old man was admitted for investigation
  of possible bronchogenic carcinoma
• Serum Ref range
• Sodium 121 mmol/L 133 143
• Potassium 4.1 mmol/L 3.6 4.6
• Urea 4.4 mmol/L 3.0 7.0
• Glucose 5.2 mmol/L
• Osmolality 250 mmol/Kg 275 - 295
• Urine
• Osmolality 614 mmol/Kg

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SYNDROME OF INAPPROPRIATE ADH

• Hyponatraemia is very common
• up to15 hospitalised patients
• affects 50 of nursing home residents each year
• gt30 acutely ill nursing home patients have
  hyponatramia
• SIADH accounts for about 50 of all chronic
  hyponatraemias

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SYNDROME OF INAPPROPRIATE ADH

• Bartter and Schwartz criteria (1967)
• hyponatraemia with hypotonicity of plasma
• urine osmolality inappropriately high
• ongoing renal sodium excretion
• absence of oedema or volume depletion
• normal renal and adrenal function
• i.e. normovolaemic hyponatraemia

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SYNDROME OF INAPPROPRIATE ADH
Symptoms relate to rate of fall as well as
severity

• Sodium lt120 mmol/L
• Lethargy
• Anorexia
• Nausea and vomiting
• Irritability
• Headache
• Muscle weaknes
• Cramps

• Sodium lt110 mmol/L
• Drowsiness
• Confusion
• Depressed reflexes
• Extensor plantar responses
• Seizures
• Coma
• Death

No oedema because water distributed in both
compartments
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SIADH - pathogenesis

• Inappropriately high AVP levels
• Ongoing (unregulated) water intake
• Blood volume rises
• gt10 expansion inhibits aldosterone and triggers
  natriuresis

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Causes of SIADH

• Neoplasia
• Carcinoma of lung, pancreas, bladder
• Leukaemia
• Thymoma
• Lymphoma
• Sarcoma
• Mesothelioma

• Neurological disorders
• Meningitis
• Encephalitis
• Brain tumour
• Subarachnoid haemorrhage
• Cerebral and cerebellar atrophy
• Guillain-Barré syndrome
• Acute intermittent porphyria
• Shy-Drager syndrome
• Head injury

• Lung disease
• Pneumonia
• TB
• Pneumothorax
• Asthma
• IPPV

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Causes of SIADH

• Drugs
• Vasopressin
• Oxytocin
• Vinca alkaloids
• Cisplatin
• Chlorpropamide
• Carbamazepine
• Phenothiazines
• Thiazides
• MAOIs
• SSRIs
• Tricyclics
• Nicotine
• Ecstacy

• Miscellaneous
• Acute psychosis
• Post-operative state
• AIDS
• Glucocorticoid deficiency
• Severe hypothyroidism
• Idiopathic

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The impact of ageing on water metabolism

• Rise in osmotic sensitivity of ADH release
• Delayed ability to excrete water load
• Thirst mechanism diminishes
• Decrease in maximal urinary concentrating ability
• Decreased renal mass
• Impaired responsiveness to sodium balance
• Multiple drug therapy
• A lifetime of accumulated disease and
  comorbidities

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The impact of ageing on water metabolism

• Rise in osmotic sensitivity of ADH release
• Delayed ability to excrete water load
• Thirst mechanism diminishes
• Decrease in maximal urinary concentrating ability
• Decreased renal mass
• Impaired responsiveness to sodium balance
• Multiple drug therapy
• A lifetime of accumulated disease and
  comorbidities

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Patterns of AVP release in SIADH
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Diagnosis of SIADH

• Essential criteria
• True plasma hypo-osmolality (lt275 mOsm/Kg)
• Inappropriate urine osmolality (gt100 mOsm/Kg)
• Euvolaemia no oedema, ascites or intravascular
  hypovolaemia
• Urine sodium not low (gt30 mmol/L during normal
  intake)
• Normal renal, adrenal, and thyroid function
• Supplemental criteria
• Low serum urea and urate
• Unable to excrete gt80 of water load (20mL/Kg) in
  4h and/or failure to achieve urine osmolality
  lt100 mOsm/Kg
• No significant rise in serum Na after volume
  expansion but improvement with fluid restriction

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Treatment of SIADH

• Identification and treatment of underlying cause
• Clearance of excess water
• not necessary in asymptomatic chronic
  hyponatraemia
• fluid restriction to 500 - 1000 mL/24h
• Demeclocycline
• 600 to 1,200 mg daily
• may take three weeks to reach maximal effect
• caution in renal or hepatic insufficiency
• Specific V2 receptor antagonists (OPC-31260)

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Treatment of SIADH

• Hypertonic saline
• Only if significantly symptomatic or duration lt3
  day
• Calculate sodium required
• Na req. (mmol) (125 Na) x 0.6 x body
  weight (kg)
• Also measure and re-infuse urinary sodium output
• Rate of increase not usually gt0.5 mmol/L/h
• ? combine with i.v. furosemide
• Stop saline when sodium reaches 120 - 125 mmol/L

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Treatment of SIADH
Na req. (mmol) (125 Na) x 0.6 x body
weight (kg)

• Example symptomatic patient with sodium 105
  mmol/L
• Body weight 60 Kg
• Available hypertonic saline 2.7 (3 normal)
• Sodium requirement (125-105) x 0.6 x 60 720
  mmol
• 2.7 saline Na 462 mmol/L
• Correction at 0.5 mmol/L/hr ? correction over 25
  hrs
• 2.7 saline requirement 720/462 L 1.56 L
• Infusion rate 1.56/25 62 mL/hr (plus extra for
  ongoing urinary Na output)

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Other causes of euvolameic hyponatraemia

• Psychogenic hyponatraemia
• Massive water intake (20 - 30 L/day)
• Urine osmolality lt100 mOsm/kg
• Beer-drinkers potomania
• High volume low solute drinks impair ability to
  excrete water
• Hypothyroidism
• Reset osmostat
• Pure glucocorticoid deficiency
• Cortisol is required for renal free water
  excretion

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Cerebral salt wasting

• SIADH
• 1º increase in AVP
• Inappropriate urine hyperosm.
• Volume-expansion
• Suppressed aldosterone
• Appropriate natriuresis
• Decreased urea and urate
• Treatment fluid restriction

• CSW
• Cerebral damage
• Reduced SNS efferents /- BNP
• Inappropriate natriuresis
• Volume-depletion
• Volume mediated AVP release
• Appropriate urine hyperosm.
• Treatment Normal saline infusion

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Case 4

• A 53-year old bachelor was brought to the AE
  department having been found semi-comatose. He
  was known to be a heavy drinker of alcohol. On
  examination he was jaundiced. His abdomen was
  distended there was hepatomegaly and evidence of
  ascites. He had ankle oedema.
• Serum Ref range
• Creatinine 84 µmol/L 75 120
• Urea 10.0 mmol/L 3.0 7.0
• Sodium 111 mmol/L 133 143
• Potassium 4.9 mmol/L 3.6 4.6
• Bilirubin 166 µmol/L lt 17
• Alk phos 175 U/L 21 - 92
• ALT 450 U/L 5 40
• Albumin 24 g/L 35 55
• Total protein 72 g/L 62 80
• Globulin 48 g/L 22 - 36

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Oedematous hyponatraemia

• Splanchnic arterial underfilling / vasodilatation
• ?
• Non-osmotic release of AVP
• ?
• Impaired renal water retention
• ?
• Dilutional hyponatraemia