10. Physiology of Thirst and Fluid Balance and its Disorders

Question 1

What hormone is featured in regulating thirst and fluid balance?

Answer 1

Anti-diuretic hormone (ADH) aka arginine vasopressin (AVP)

Question 2

Why is water homeostasis important?

Answer 2

Regulating water ensures plasma osmolality and extracellular fluid osmolality remains stable.
There is a very narrow range of plasma osmolality - 285-295mosmol/kg

Question 3

What are the 3 key determinants of water balance?

Answer 3

ADH - osmotically stimulated secretion, acts on renal tubule to allow changes in water excretion.

Kidney - wide variation in urine output (0.5-20 L/day)

Thirst - osmoregulated, stimulates fluid intake

Question 4

What are osmoreceptors

Answer 4

Groups of specialised cells which detect changes in plasma osmolality, especially Sodium.

Located in the anterior wall of the third ventricle. Fenestrations in the blood brain barrier allow circulating solutes aka osmoles, to influence brain osmoreceptors

Osmoreceptor cells alter their volume by a transmembrane flux of water in response to changes in plasma osmolality

This initiates neuronal impulses that are transmitted to the hypothalamus to synthesise ADH and to the cerebral cortex to register thirst

Question 5

Anti-diuretic hormone (ADH)

Answer 5

ADH = against a diuresis - water conserving
Human form of ADH is arginine vasopressin (AVP)

Like oxytocin:
nonapeptide (9 aa)
Vasopressin synthesised in neurons in supraoptic and paraventricular nuclei of hypothalamus
Secretory granules migrate down axons to posterior pituitary from where AVP is released

Question 6

What is AVP

Answer 6

AVP (arginine vasopressin) is human ADH
AVP = ADH
ADH = AVP=vasopressin
same thing

stops u peeing

desmopressin = synthetic vasopressin/AVP

Question 7

Where are oxytocin and AVP synthesised?

Answer 7

In supraoptic and paraventricular nuclei of hypothalamus

Secretory granules migrate down axons to posterior pituitary, where AVP is releases from

Question 8

ADH action in the kidney

Answer 8

ADH action is mediated via V2 receptors

Aquaporins (ADH-sensitive water channel) are normally stored in cytoplasmic vesicles but move to and fuse with luminal membrane in response to ADH

ADH increases water permeability of renal collecting tubules, promoting water reabsorption

When ADH is cleared, water channels are endocytosed from the luminal surface and return to the cytoplasm

Question 9

Low plasma osmolality

Answer 9

(lots of water little osmoles)
AVP is undetectable
Dilute urine
High urine output
No thirst

Question 10

High plasma osmolality

Answer 10

(little water lots of osmoles)
High AVP secretion
Concentrated urine
low urine output
Increased thirst sensation

Drinking immediately transiently suppresses AVP secretion and thirst to avoid overshoot

Question 11

Polyuria and polydipsia (diabetes insipidus)

Answer 11

Exclude diabetes mellitus

Three main causes:
Cranial (central) diabetes insipidus (DI): lack of osmoregulated AVP secretion/lack of vasopressin

Nephrogenic diabetes insipidus:
lack of response of renal tubule to AVP

Primary polydipsia: psychogenic polydipsia, social/cultural (e.g. drinking too much/too little water), loss of thirst centre stimulation

All may be partial

Question 12

Primary causes of cranial diabetes insipidus

Answer 12

27% idiopathic

<5% genetic - familial (AD) mutation of AVP gene, DIDMOAD (Wolfram) (Ar, incomplete penetrance)

Question 13

Secondary causes of causal diabetes insipidus

Answer 13

Post-surgical (pituitary/other brain operations)
Traumatic (head injury, including closed injury)
Rarer causes - tumours, histiocytosis, sarcoidosis, encephalitis, meningitis, vascular insults, autoimmune
Decreased osmoregulated AVP secretion
Excess solute-free renal water excretion -polyuria
Provided thirst sensation remains intact and there is ready access to fluids, thirst is stimulated to maintain a stable, normal plasma osmolality - polydipsia

Question 14

Hypothalamic syndrome

Answer 14

Disordered thirst and DI, disordered appetite (hyperphagia), disordered temperature regulation, disordered sleep rhythm, hypopituitarism

Question 15

Nephrogenic diabetes insipidus

Answer 15

Renal tubules resistant to AVP - polyuria
Thirst stimulated - polydipsia
Idiopathic
Genetic (rare) Xr or Ar - mutations of V2 receptor gene/aquaporin gene
Metabolic - high [Calcium] or low [Potassium]
Drugs - lithium
Chronic kidney disease

Question 16

Primary polydipsia (psychogenic)

Answer 16

increased fluid intake -polydipsia
Lower plasma osmolality
Suppressed AVP secretion
Low urine osmolality, high urine output - polyuria
Also lose renal interstitial solute, reducing renal concentrating ability

Question 17

What is polydipsia

Answer 17

Excessive thirst or drinking

Question 18

Investigating polyuria and polydipsia

Answer 18

Medical history
Exclude diabetes mellitus
Document 24 hour fluid balance
Urine output and fluid intake, day & night
Exclude hypercalcaemia,hypokalaemia
Water deprivation test

Question 19

What is a water deprivation test?

Answer 19

Period of dehydration
Measure plasma and urine osmolalities & weight
Injection of synthetic vasopressin - desmopressin (DDAVP)
Measure plasma and urine osmolalities

Question 20

What are the different responses in a water deprivation test?

Answer 20

Normal response to dehydration - normal plasma, osmolality, high urine osmolality

Cranial diabetes insipidus - poor urine concentration after dehydration, rise in urine osmolality after desmopressin

Nephrogenic diabetes insipidus - poor urine concentration after dehydration, no rise in urine osmolality after desmopressin

so basically if normal get conc pee, if cranial DI dont get conc pee but do with desmopressin (because problem is lack of AVP) and if nephrogenic doesnt get better even with desmopressin because can;t respond to it at kidney level anyway

Question 21

Treatment of DI

Answer 21

Cranial:
DDAVP (desmopressin) but over-treatment can cause hyponatraemia

Nephrogenic:
Correction of cause (metabolic/drug cause)
Thiazide diuretics/NSAIDs

Primary polydipsia:
Explanation, persuasion
Psychological therapy

Question 22

Hyponatraemia definition

Answer 22

[Sodium] < 135mmol/L

Severe [Na] <125 mmol/L

Question 23

Symptoms of hyponatraemia

Answer 23

May be asymptomatic
Depends on rate of fall as well as absolute value
Brain adapts if chronic

Non-specific: headache, nausea, mood change, cramps, lethargy

Severe/sudden: confusion, drowsiness, seizures, coma

Question 24

Classification of hyponatraemia

Answer 24

Exclude drug causes e.g. thiazide diuretics
Exclude high concentrations of glucose, plasma lipids or proteins

Classify by extracellular fluid volume status:
hypovalaemia: renal loss, non-renal loss (D&V, burns, sweating)

Normovalaemia (euvolaemia): hypoadrenalism, hypothyroidism, SIADH

Hypervolaemia: renal failure, cardic failure, cirrhosis, excess IV dextrose

Question 25

SIADH

Answer 25

Clinically euvolaemic patient, with low plasma sodium and low plasma osmolality
inappropriately high urine sodium concentration and high urine osmolality (normal volume of blood with low sodium, but lots of sodium in pee)

Assess renal, adrenal and thyroid function
Many causes: neoplasias, neurological disorders (CNS), lung disease, drugs, endocrine (hypothyroid/hypoadrenalism)

Question 26

SIADH treatment

Answer 26

Identify and treat underlying cause

Fluid restriction (<100ml daily)
Induce negative fluid balance 500ml
Aim for a low-normal sodium

Demeclocycline - drug that induces mild nephrogenic DI

Vasopressin (V2R) antagonists - vaptans that induce a water diuresis. Expensive, variable responses, some attenuation. Lack of clinically significant outcome data

Question 27

Hyponatraemia treatment

Answer 27

Correct severe hyponatraemia slowly
Rapid correction risks oligodendrocyte degeneration and CNS myelinolysis (osmotic demyelination)
-> severe neurological sequelae, may be permanent. Alcoholics & malnourished particularly at risk