AVP deficiency (diabetes insipidus)

Terminology

• Hypotonic polyuria-polydipsia syndrome is an umbrella term which incorporates AVP deficiency, AVP resistance and primary polydipsia
• AVP (arginine vasopressin) and ADH (antidiuretic hormone) are the same. The two names are used interchangeably
• The term Diabetes Insipidus is outdated.
• AVP deficiency (formerly central diabetes insipidus) is typically due to hypothalamic-posterior pituitary disruption or injury
• This may be secondary to neurosurgery, trauma, tumours, infiltrative disease, autoimmunity, vascular events, or genetic defects
• AVP resistance was formally known as nephrogenic DI

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Features

• AVP deficiency leads to an inability of the kidneys to concentrate urine
• Clinically it causes hypotonic polyuria (including frequent nocturia), compensatory polydipsia (can be sudden onset), and a risk of severe dehydration if water access is impaired
• Biochemically 
  • • Serum osmolality > 300
    • Urine osmolality < 600 (often < 100).
    • Urine Na < 20 and urine specific gravity < 0.02
    • Serum Na will be normal if there’s compensatory polydipsia and the patient can drink enough
    • Low sodium and low serum osmolality (<274) in contrast suggests primary polydipsia
• Ask about
  • • Fluid intake (pyschogenic polydipsia an important differential) and urinary frequency
    • Pituitary surgery
    • Headaches
    • Renal disease
    • Medications
    • Symptoms of hypopituitarism
• Check urine volume. Patients can pass 16L of dilute urine/day, but always > 3L. The urine will appear like water.
• Sodium should be normal unless patient not allowed to drink or not able. If Na low this suggests too much desmopressin or fluids, and if Na high this suggests not enough desmopressin or fluids.

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Causes of AVP deficiency or resistance

• Renal (resistance to ADH)
  • • Inherited (x-linked recessive) – including defects in ADH and aquaporin receptor
    • Renal issues – PCKD, chronic pyelonephritis, post-obstruction, Fanconi’s syndrome, T2 Renal Tubular Acidosis
    • Chronic hypercalcaemia, chronic hypokalaemia
    • Drugs (especially lithium toxicity, but also gentamycin, demeclocycline, amphotericin, glibenclamide)
    • Sarcoid, amyloid, sickle cell disease
• Cranial (low ADH) – aka AVP deficiency
  • • Hypopituitarism
    • Space occupying lesions
    • Inherited (AD)
    • Idiopathic (20%, some likely autoimmune)
    • DIDMOAD
    • Cranial trauma, post brain surgery (commonest, can be transient), radiotherapy
    • Aneurysms/SAH
    • Cerebral infection
    • Hypothalamic infiltration (LCH, sarcoid, TB)
    • Hypophysitis (inflammatory, autoimmune, IgG4 related)
• Dipsogenic – due to similar causes to the cranial aetiologies, due to hypothalamic damage and change in thirst mechanism
• Gestational – associated with pre-eclampsia, HELLP, fatty liver. Usually treated with DDAVP

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Investigations

• Check glucose
• Check K+ (hypokalaemia causes AVP resistance)
• Check calcium – can be high
• Serum and urine osmolality, urinary Na
• Calculate the free water deficit especially if reduced GCS
• Consider doing a fluid/water deprivation test for a formal diagnosis (may be very uncomfortable for the patient)
  • • In some centres copeptin levels have replaced this
    • Don’t need to do one if serum osmolality already very high
    • More useful if you want to push up their serum osmolality and measure what happens to their urine osmolality – to check if it’s a normal response
• Send full pituitary screen if possible cranial cause (including TSH, cortisol, ACTH, sex hormones, prolactin, IGF-1).
• Consider MRI pituitary
• Can’t measure ADH (degrades quickly) but can measure copeptin which is a surrogate (this may take several weeks to come back)
• Copeptin
  • >5.6 pmol/l in primary polydipsia
  • <4.9 pmol/l in AVP deficiency
  • >21.4 pmol/l in AVP resistance
• Urine osmolality is a key test – if very high, it suggests another diagnosis
• Diagnostic score in development
• Primary polydipsia is a differential
  • • Doesn’t only occur in psychiatric conditions, can also occur in hypothalamic dysfunction, or in health conscious people who drink a lot of water
    • Over time it can mimic AVP deficiency biochemically (chronic high intake of water suppresses endogenous AVP release)

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Treatment

• Treat if hypernatremic and dry
• Strict fluid balance, urinary catheter
• IV fluids – can alternate saline and dextrose. Can match hourly urine output plus 200-500ml, or maintain neutral fluid balance
• Trust that their thirst instinct will allow them to drink enough
• Any fluid is fine, but give enough (‘people die from DI’)
• Aim not to reduce Na too fast (although is Na has increased rapidly ie over hours, might be safe to bring it down fast)
• HDU might be best for close monitoring
• VTE prophylaxis
• Treat cranial causes with desmopressin (DDAVP)
  • • Dose is 1mcg subcutaneously, or 100 mcg PO, or 10 mcg nasally
    • Subcutaneous dose is effective for 12-18 hours
    • Monitor Na to make sure not overtreated (ie going low, which is common)
• If nephrogenic DI
  • • Then desmopressin won’t work, but this condition usually not as severe
    • Can be difficult to manage
    • Can try a thiazide diuretic (paradoxically) plus an NSAID
• Any patient admitted on DDAVP needs to be taken very seriously – it’s a life sustaining drug
  • • Ensure DDAVP sourced and administered, and that nursing staff are aware of its importance
    • Immaculate fluid balance chart and ensure access to drinking water
    • If low Na consider omitting next dose of DDAVP, if high Na consider 5% dextrose and drink to thirst
    • If a patient is nil-by-mouth or vomiting – convert DDAVP to nasal or injection (doses are different, see conversion above).
    • There are lots of serious incidents associated with poor management of AVP deficiency. Get specialist advice early.