Transcript Aldosterone as a Risk Factor for Metabolic Syndrome

Diabetes Insipidus
Endocrinology Rounds
November 4, 2009
Selina Liu
PGY4 Endocrinology
Objectives
 To understand and describe the
pathophysiology of diabetes insipidus
 To be able to diagnose and treat
diabetes insipidus
Objectives
 To name this statue, and
its location
 EXTRA CREDIT: to learn
when this statue was built
Outline
 Background
 Vasopressin Physiology
 Definition & Classification of Diabetes Insipidus (DI)
 Central Diabetes Insipidus
 Causes & Pathophysiology
 Approach to Polyuria & Diagnosis of DI
 Treatment
Background - Vasopressin
 Arginine Vasopressin (AVP) or Antidiuretic Hormone (ADH)
 polypeptide hormone
 synthesized in magnocellular neurons originating in
hypothalamic nuclei - supraoptic and paraventricular
 neurons terminate on capillaries of inferior hypophyseal
artery of posterior pituitary
 rapidly metabolized in liver & kidneys - t1/2 15-20 min
Kronenberg HM et al. 2008 Williams Textbook of Endocrinology. 11th edition.
http://www.colorado.edu/intphys/Class/IPHY3430-200/image/figure1806.jpg
Background – Vasopressin Effects
 mediated via GPCRs - vasopressin receptors V1,V2,V3
 V1 – vascular smooth muscle (liver, platelets, CNS)
- increase peripheral vascular resistance
- stimulate prostaglandin synthesis
- stimulate liver glycogenolysis
 V2 – renal
- increase H2O permeability of the renal collecting duct
epithelium via aquaporin-2
- stimulate vascular endothelial release of vWF, FVIII
 V3 – pituitary
- potentiate action of CRH  ACTH release
Background – Vasopressin Effects
 main effects:
 regulation of water
homeostasis and osmolality
of body fluids
 cardiovascular effects
http://www.healthsystem.virginia.edu/internet/dab_lab/lecture_notes/pdf/adh.pdf
http://www.dmcg.edu/phpbb2/lofiversion/index.php?t615.html
Background – Vasopressin Regulation
Osmoregulation:
 osmoreceptors in hypothalamus
 sense increase in plasma osmolality
 increase thirst and vasopressin secretion
 increase fluid intake and water retention
Ball SG. 2007 Ann Clin Biochem 44:417-431
Ball SG. 2007 Ann Clin Biochem 44:417-431
Background – Vasopressin Regulation
Osmoregulation:
www.utdol.com
Background – Vasopressin Regulation
Baroregulation:
 baroreceptors in carotid sinus
(also in left atrium – to lesser degree)
 sense decrease in effective circulating volume by
resultant decrease in cardiac output
 less sensitive than osmoreceptors:
- small changes in ECV – stimulate RAAS
- only large changes in ECV – stimulate vasopressin
secretion via baroreceptor
Background – Vasopressin Regulation
Baroregulation:
www.utdol.com
Background – Vasopressin Regulation
 physiological & pathological factors affecting
vasopressin secretion:
www.utdol.com
0.5 pmol/L
maximum
diuresis
3-4 pmol/L
maximum urine
concentration
Ball SG. 2007 Ann Clin Biochem 44:417-431
Diabetes Insipidus - Definition
 insipidus – Latin (in + sapidus) – “tasteless”
 characterized by large volume of hypotonic, dilute,
tasteless urine
 diabetes mellitus – hypertonic & sweet urine
 polyuria – urine output >40ml/kg/day or >3L/day
Diabetes Insipidus: Classification
 4 pathophysiological mechanisms:
 Primary Polydipsia
(Dipsogenic DI vs. Psychogenic Polydipsia)
 Nephrogenic Diabetes Insipidus
 Transient Diabetes Insipidus of Pregnancy
 Central Diabetes Insipidus
(Hypothalamic or Neurohypophyseal DI)
Dipsogenic Diabetes Insipidus
 abnormality in osmoregulation of thirst
 ingestion of excessive volumes of fluid
 suppression of vasopressin release  polyuria
 causes:
 idiopathic
 infiltrative (sarcoidosis)
 autoimmune (MS)
 drug-induced (lithium, TCAs)
 vs. psychogenic polydipsia – no abnormality in thirst?
Nephrogenic Diabetes Insipidus
 renal resistance to vasopressin
 plasma vasopressin levels normal or elevated
 causes:
 chronic renal disease (any disorder interfering with collecting
duct or medullary function i.e. PCKD, pyelonephritis)
 familial/congenital – mutations in V2R, aquaporin-2 genes
 drugs – lithium, demeclocycline, colchicine, gentamicin
 hypercalcemia, hypokalemia
 multiple myeloma, sickle cell anemia, Sjögren’s
Transient DI of Pregnancy
Normal pregnancy:
 reset osmostat  plasma Na decreased by 5 mEq/L
mediated by increase in hCG
 increased catabolism of vasopressin due to cysteine
aminopeptidase (vasopressinase) produced by placenta
vasopressin levels usually remain normal due to increased
production of vasopressin
 water retention - fall in plasma osmolality 10 mOsm/kg
 vasopressin release and osmotic threshold for thirst also
decrease in parallel
Transient DI of Pregnancy
 2 types of DI in pregnancy
 “vasopressin-resistant DI of pregnancy”
 increased vasopressinase levels and activity
 associated with pre-eclampsia, AFLP
 accelerated catabolism of vasopressin in women
with underlying borderline vasopressin function
(i.e mild nephrogenic DI or partial central DI)
 related to limited neurohypophyseal secretory reserve
Central Diabetes Insipidus
 deficient vasopressin secretion
 can cause variable degree of polyuria
 defect at > 1 site involved in vasopressin secretion:
 hypothalamic osmoreceptors
 supraoptic or paraventricular nuclei
 pituitary stalk
Makaryus AN & McFarlane SI
2006 Clev Clin J Med 73:(1)65-71
Central Diabetes Insipidus - Causes
 Idiopathic
 Familial
 Trauma or Neurosurgery
 Malignancy
 Infiltrative
 Hypoxic encephalopathy
 Other
Idiopathic Central Diabetes Insipidus
 destruction of hypothalamic secretory cells
 ? autoimmune
 cytoplasmic autoantibodies to vasopressin cells
 lymphocytic infiltration of posterior pituitary & stalk
 may also have anterior pituitary deficiency
 possibly represents occult pathological process
pts with idiopathic CDI who develop anterior pituitary deficiency
years later may have pituitary or sellar tumour
Familial Central Diabetes Insipidus
 autosomal dominant – mutation in AVP gene
 accumulation of misfolded AVP precursors in ER
 potentially toxic  autophagy activated
 results in apoptosis
 progressive deficiency of vasopressin
 signs & symptoms develop months to years after birth
Post-Operative or Post-Trauma DI
 transient DI within 24 hrs of pituitary surgery
up to 50-60% of pts, usually resolves
 if complete stalk section, can have triphasic response
 initial polyuric phase – due to inhibition of vasopressin
release due to hypothalamic dysfunction,
- within first 24 h, lasts 4-5 d
 antidiuretic phase – due to release of stored hormone
- from day 6-12
 return of diabetes insipidus
Kronenberg HM et al. 2008 Williams Textbook of Endocrinology. 11th edition.
Post-Operative or Post-Trauma DI
 estimated incidence post-pituitary surgery:
 minimally invasive (endoscopic trans-nasal resection)
 permanent 2.7%, transient 13.6%
 elevated serum Na >145 within 5 days of surgery was
predictive of developing permanent DI
 sensitivity 87.5%, specificity 83.5%, NPV 99.5%
 other risk factors: Rathke’s cleft cyst histology,
intraoperative CSF leak, prev non-endoscopic resection
Sigounas DG et al. 2008. Neurosurg 62:71-79
Other Causes of Central DI
 Malignancy – both solid & hematological
- 1o and metastatic
 Infiltrative – Langerhans cell histiocytosis, sarcoidosis,
autoimmune lymphocytic hypophysitis, Wegener’s
 Hypoxic encephalopathy – cardiac arrest, shock,
Sheehan’s syndrome
 post-SVT correction – decreased AVP, increased ANP
 anorexia nervosa
 Acute Fatty Liver of Pregnancy
Wolfram’s Syndrome (DIDMOAD)
 DIDMOAD – autosomal recessive
 mutations in WFS1 (Wolframin) and ZCD2 genes
encode endoplasmic reticulum proteins, involved
in calcium homeostasis
 Diabetes Insipidus – loss of AVP secreting neurons in
supraoptic nuclei, impaired processing of AVP precursors
 Diabetes Mellitus
 Optic Atrophy
 Deafness
Approach to Polyuria
 History
 onset/rate of polyuria, FMHx, medications
 rule out other causes (osmotic diuresis, post-obstructive,
diuretics, nocturia due to BPH etc.)
 Physical Exam
 fluid status assessment
 Lab Investigations
 serum & urine electrolytes, osmolality
Lab Investigations
Lab Test
Central DI
Nephrogenic DI
Psychogenic Polydipsia
Plasma osmolality



Urine osmolality



urine osm < plasma osm
Water Deprivation Test
 to confirm DI
 to distinguish between central vs. nephrogenic
 can be done as outpatient through CIU
 under closely monitored conditions
 medications that may interfere with results:
 lithium, phenothiazines, cyclophosphamide, TCAs,
phenytoin, carbamazepine, clonidine
Water Deprivation Test
 check baseline weight, BP, serum & urine osm, lytes
 NPO (timing depends on individual)
 q 1 hrs: weight, BP, urine volume & osmolality
 q 2 hrs: plasma lytes & osmolality
Water Deprivation Test
 continue until 1 of the following occurs:
 weight decreases by > 5%
 urine osmolality increases < 30 mosmol/kg for 3 hrs
 serum Na > 150 mmol/L
 plasma osmolality > 300 mosmol/kg
 significant decrease of BP
 urine osmolality > 600 mosmol/kg
Water Deprivation Test
 if any of these criteria met (except urine osmol >600)
 give DDAVP 10 mg intranasal
 check urine & serum osmolality 1 h post-DDAVP
Water Deprivation Test - Interpretation
 Complete Central DI
 urine osmolality will be minimally concentrated despite
dehydration
 will have significant increase in urine osmolality in response to
dDAVP (at least 50%, up to 200-400%)
 undetectable vasopressin levels at end of dehydration
 Complete Nephrogenic DI
 also minimal urine concentration despite dehydration
 LITTLE/NO response of urine osmolality to dDAVP
 HIGH vasopressin levels at end of dehydration
Water Deprivation Test - Interpretation
 Partial Central DI vs. Primary Polydipsia – can be difficult
 both – urine will concentrate with dehydration
 often above plasma osmolality
 but does not approach 800-1000 mOsm/kg (normal)
 after dDAVP – in Partial Central DI, may have further
concentration of urine (at least 10%) but no further
increase in Primary Polydipsia
 some pts with partial central DI – may be hyperresponsive to
submaximal rise in AVP with dehydration (?receptor upregulation),
so may not have response to exogenous dDAVP
Nussey SS & Whitehead SA.
Endocrinology An Integrated
Approach 2001
Example – Water Deprivation Test
? Diagnosis
Treatment – Nephrogenic DI
 maintain adequate water intake
 dietary salt restriction, diuretics (thiazides), NSAIDS
 (if partial sensitivity, can use desmopressin)
GOAL – to maintain mild state of sodium depletion
 reduce solute load on kidney
 enhance proximal tubular reabsorption
 minimize loss of water
Treatment – Transient DI of Pregnancy
 Desmopressin – synthetic analogue of vasopressin
not catabolized by vasopressinase
 has 2-25% oxytocic activity of vasopressin
so minimal stimulation of oxytocin receptors of uterus
 safe for mother & fetus
 close monitoring of fluid status during delivery
 post-partum, plasma vasopressinase decreases
 may resolve or become asymptomatic
Treatment – Central DI
GOAL – decrease thirst & polyuria to acceptable levels
 decrease interference on lifestyle
 avoid overtreatment (risk of hyponatremia)
 only drink when thirsty
 most people with intact thirst mechanisms will be able
to maintain adequate water intake
 caution in elderly, those with disrupted thirst mechanisms
Treatment – Central DI
Medications:
 Desmopressin (DDAVP)
 nasal spray/solution, oral tablet/melt, sc injection
 if partial central DI:
 chlorpropamide
 carbamezepine
 clofibrate
 thiazide/NSAID
Treatment – Central DI
 desmopressin acetate - DDAVP
 Spray – metered dose 10 mg nasal spray (10-40 mg daily)
 Rhinyle – 0.1mg/ml nasal solution (0.05ml = 5mg)
 Tablets - 0.1 or 0.2 mg tablets (max 1.2 mg daily)
 Injection - 1-4 mg sc daily
 Melts - 60, 120, 240 mg oral disintegrating tablets
 titrate to symptoms – start at hs to control nocturia
 monitor polyuria, timing of “breakthrough”
 daily weights may be helpful
Treatment – Central DI
 chlorpropamide – 250-500 mg daily
 long-acting sulfonlyurea
 promotes renal response to vasopressin
 carbamazepine – 100-300 mg bid
 anti-epileptic
 enhance renal response to vasopressin
 clofibrate – 500 mg q 6h
 fibrate
 increases vasopressin release
 thiazide or NSAID
Post-Neurosurgery - Protocol
Outline
 Background
 Vasopressin Physiology
 Definition & Classification of Diabetes Insipidus (DI)
 Central Diabetes Insipidus
 Causes & Pathophysiology
 Approach to Polyuria & Diagnosis of DI
 Treatment
Objectives
 Manneken Pis
(aka Petit Julien)
References
 www.uptodate.com
 Kronenberg HM et al. Williams Textbook of Endocrinology. 11th
edition. 2008 Saunders Elsevier.
 Ball SG. 2007. Ann Clin Biochem 44:417-431
 Makaryus AN & McFarlane SI. 2006. Clev Clin J Med 73:(1)65-71
 Sigounas DG et al. 2008. Neurosurg 62:71-79
 Nussey SS & Whitehead SA. Endocrinology An Integrated
Approach 2001
 http://www.colorado.edu/intphys/Class/IPHY3430-200/image/figure1806.jpg
 http://www.healthsystem.virginia.edu/internet/dab_lab/lecture_notes/pdf/adh.pdf
 http://www.dmcg.edu/phpbb2/lofiversion/index.php?t615.html