Diabetes Insipidus

1. Diabetes Insipidus Endocrinology Rounds November 4, 2009 Selina Liu PGY4 Endocrinology

2. Objectives • To understand and describe the pathophysiology of diabetes insipidus • To be able to diagnose and treat diabetes insipidus

3. Objectives • To name this statue, and its location • EXTRA CREDIT: to learn when this statue was built

4. Outline • Background • Vasopressin Physiology • Definition & Classification of Diabetes Insipidus (DI) • Central Diabetes Insipidus • Causes & Pathophysiology • Approach to Polyuria & Diagnosis of DI • Treatment

5. 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.

6. http://www.colorado.edu/intphys/Class/IPHY3430-200/image/figure1806.jpghttp://www.colorado.edu/intphys/Class/IPHY3430-200/image/figure1806.jpg

7. 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

8. 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

9. http://www.dmcg.edu/phpbb2/lofiversion/index.php?t615.html

10. Background – Vasopressin Regulation Osmoregulation: • osmoreceptors in hypothalamus • sense increase in plasma osmolality • increase thirst and vasopressin secretion • increase fluid intake and water retention

11. Ball SG. 2007 Ann Clin Biochem 44:417-431

12. Ball SG. 2007 Ann Clin Biochem 44:417-431

13. Background – Vasopressin Regulation Osmoregulation: www.utdol.com

14. 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

15. Background – Vasopressin Regulation Baroregulation: www.utdol.com

16. Background – Vasopressin Regulation • physiological & pathological factors affecting vasopressin secretion: www.utdol.com

17. 3-4 pmol/L maximum urine concentration 0.5 pmol/L maximum diuresis Ball SG. 2007 Ann Clin Biochem 44:417-431

18. 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

19. 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)

20. Dipsogenic Diabetes Insipidus • abnormality in osmoregulation of thirst • ingestion of excessive volumes of fluid • suppression of vasopressin release  polyuria • causes: • vs. psychogenic polydipsia – no abnormality in thirst? • idiopathic • infiltrative (sarcoidosis) • autoimmune (MS) • drug-induced (lithium, TCAs)

21. 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

22. 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

23. 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

24. 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

25. Makaryus AN & McFarlane SI 2006 Clev Clin J Med 73:(1)65-71

26. Central Diabetes Insipidus - Causes • Idiopathic • Familial • Trauma or Neurosurgery • Malignancy • Infiltrative • Hypoxic encephalopathy • Other

27. 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

28. 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

29. 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

30. Kronenberg HM et al. 2008 Williams Textbook of Endocrinology. 11th edition.

31. 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

32. 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

33. 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

34. 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

35. Lab Test Central DI Nephrogenic DI Psychogenic Polydipsia Plasma osmolality    Urine osmolality    urine osm < plasma osm Lab Investigations

36. 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

37. 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

38. 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

39. 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

40. 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

41. 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

42. Nussey SS & Whitehead SA. Endocrinology An Integrated Approach 2001

44. Example – Water Deprivation Test ? Diagnosis

45. 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

46. 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

47. 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

48. Treatment – Central DI Medications: • Desmopressin (DDAVP) • nasal spray/solution, oral tablet/melt, sc injection • if partial central DI: • chlorpropamide • carbamezepine • clofibrate • thiazide/NSAID

49. 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

50. 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