ADH / Posterior Pituitary

Question 1

ADH Production/Secretion/Action

Answer 1

• Formed in special neurons of hypothalamus (supraoptic and paraventricular nuclei)–> put into secretory vesicles (processing) then transported via axons to posterior pituitary –> release when these bodies are depolarized and propogate down axon
• Binds V2R receptors of basolateral distal nephron –> GPCR –> inc cAMP –> AQ2 channels made and transferred to apical membrane to inc water reabsorption

Question 2

Central DI + Causes

Answer 2

problem w/ ADH prod

• Surgery, head injury, tumor, vascular/hemorrhage, infection, granuloma, drugs
• Genetics - rare; mutations in AVP-NP2 gene that encodes vasopressin precursor (auto dominant or auto recessive); Wolfram syndrome (DIDMOAD - DI, DM, optic atrophy, deafness)

USUALLY RAPID ONSET

Question 3

Nephrogenic DI + Causes

Answer 3

ADH resistance at V2R receptor

• Genetics/Inherited - rare; abnormal V2R (most common heritable DI; X-linked recessive), abnormal AQ2 folding
• Drugs - lithium (downregulate AQ2 production and downregulate V2R receptors), amphotercin B, cisplatin, etc
• Metabolic - chronic hypercalcemia or chronic hypokalemia

USUALLY MORE INSIDIOUS ONSET

Question 4

Primary Polydipsia

Answer 4

• psychogenic inc in water intake (schizophrenia), suppresses ADH b/c volume expansion

Question 5

Regulation of ADH

Answer 5

• Osmoreceptors (in hepatic portal vein and areas around 3rd ventricle) detect osmolality
  
  • 1-2% inc osmolality - inc synthesis and production of ADH –> inc urine osmolality
    
    • Urine osmolarity is an easier measure for monitoring
  • 2-3% inc osmolality - thirst
• Stretch receptors in heart and large arteries detect changes in blood volume; if LARGE change in blood volume of 15-20% (ex - hemorrhage) then LARGE inc in ADH –> vasopressive/ constriction effects on arterioles
  
  • Aortic arch and carotid sinus
  • V1a receptors on smooth muscle of arterioles

Question 6

Triphasic Response

Answer 6

• (ex - post hypothalamus injury or after surgery damage)
• 1- ADH release is interrupted –> transient DI (24-48 hrs after)
• 2- Wallerian degeneration of axons –> release of all pre-formed ADH from these neurons -> SIADH
• 3- Now cell bodies start to die and not making any new hormone –> permanent state of DI

***A lot of redundancy in these neurons so 85-90% must die for permanent DI so many patients only experience the first 2 phases

Question 7

Cortisol and DI

Answer 7

• Cortisol def can mask DI
• Glucocorticoids normally inhibit ADH synthesis and suppress AQ2 synthesis
• SO… glucocorticoid def –> inc AQ2 synthesis –> anti-diuresis which can cancel out diuresis of DI
• Give steroids to normalize then test for DI; become symptomatic once on steroids

Question 8

How to diagnose central v. nephrogenic v. primary polydipsia

Answer 8

• Induce state of dehydration (remove all fluids) and see what happens
• Central - will respond if given desmopressin (urine Osm inc)
• Nephrogenic - do not respond to desmopressin unless only partial DI (urine Osm remains low)
• Primary Polydipsia - their medullary gradient is so diluted that they still cannot conc urine a lot
• Modified Water Deprivation Test (can be done at home if very high suspicion)
  
  • No water after 9 PM then measure labs in morning
  • DI if high Na (dehydrated) yet low urine Osm in AM

Question 9

Central DI Tx

Answer 9

• Sufficient fluid intake + desmopressin (intranasal, subQ, oral) esp at night to prevent nocturia
• If adipsogenic DI (impaired thirst) - must determine fixed amount of water for them to drink; risk of hyponatremia if too much/ hypernatremia if not enough
• If Partial Central - sufficient water intake and desmopressin only when needed (peeing a lot)

Question 10

Nephrogenic DI Tx

Answer 10

• thiazide diuretics (inc Na and water reabsorption in early proximal tubule - also means less salt to distal tubule so body does not dilute urine here)
• NSAIDs inhibit renal prostaglandins which normally antagonize ADH
• Amiloride has added benefit of closing ENaC which is how lithium enters principal cells
• If Partial Nephrogenic DI - HIGH DOSE desmopressin may work

Question 11

Primary Polydipsia Tx

Answer 11

• limit fluids
• DO NOT give desmopressin (causes fluid retention and hyponatremia)
• treat underlying psych