DIABETES INSIPIDUSDIABETES INSIPIDUS

Richard Sachson MDRichard Sachson MD

Anatomy of the neurohypophysisAnatomy of the neurohypophysis

Magnetic resonance imaging of posterior pituitary Magnetic resonance imaging of posterior pituitary glandgland

Chemical structure of vasopressinChemical structure of vasopressin

The gene that encodes AVP-NP is located on the short arm of chromosome 20

Vasopressin Is Encoded in a Gene That Vasopressin Is Encoded in a Gene That Also Encodes Neurophysin II, an AVP-Also Encodes Neurophysin II, an AVP-

Binding ProteinBinding Protein

Signal Peptide AVP Neurophysin Glycopeptide

(Copeptin)

Exon 1 Exon 2 Exon 3

Its three exons encode a signal peptide, the vasopressin molecule, its neurophysin binding protein, and a terminal glycoprotein. The precursor is processed to yield equimolar quantities of vasopressin and NP II.

How Vasopressin Works

Physiologic regulation of vasopressinPhysiologic regulation of vasopressin

Plasma osmolality and plasma Plasma osmolality and plasma vasopressin concentrationvasopressin concentration

Plasma osmolality and plasma vasopressin Plasma osmolality and plasma vasopressin concentrationconcentration

Urine osmolality and plasma vasopressin Urine osmolality and plasma vasopressin concentrationconcentration

Water deprivation test in normal personWater deprivation test in normal person

Water deprivation test in diabetes insipidusWater deprivation test in diabetes insipidus

Differential Diagnosis of Hypotonic Differential Diagnosis of Hypotonic PolyuriaPolyuria

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Causes of nephrogenic diabetes insipidusCauses of nephrogenic diabetes insipidusCauses of nephrogenic diabetes insipidus Familial Autosomal recessive (rare) X-linked Acquired Drugs Amphotericin B Demeclocycline Lithium Methoxyflurane Electrolyte disorders Hypercalcemia Hypokalemia Tubulointerstitial renal disease Amyloidosis Medullary sponge kidney Obstructive uropathy Polycystic kidney disease Sickle cell disease or trait

Agents that alter the response of the Agents that alter the response of the collecting duct to vasopressincollecting duct to vasopressin

Agents that alter the response of the collecting duct to vasopressin Increased arginine vasopressin action Carbamazepine* Chlorpropamide* Chronic dehydration Nonsteroidal anti-inflammatory drugs Decreased arginine vasopressin action à-Adrenergic agents Atrial natriuretic peptide Demeclocycline† Hypercalcemia† Hypokalemia† Lithium† Prostaglandin E2 Protein kinase C *Causes the clinical syndrome of inappropriate antidiuretic hormone. †Usually associated with nephrogenic diabetes insipidus.

Most V2 Receptor Mutations Are in Most V2 Receptor Mutations Are in Transmembrane Domains of the Transmembrane Domains of the

ProteinProtein

Morello and Bichet 2001; Ann Rev Physiol 63:607

V2 Receptor is a G-protein coupled receptor with seven transmembrane domains

Genetic mutations in the aquaporin 2 geneGenetic mutations in the aquaporin 2 gene

The Rarest Form Of Inherited The Rarest Form Of Inherited Nephrogenic Diabetes Insipidus Is Nephrogenic Diabetes Insipidus Is

Due to Mutations In A Water Channel Due to Mutations In A Water Channel GeneGene

• AQP2 is encoded by a gene on chromosome 12

• Most mutations are recessive, but some transmit a dominant phenotype

Causes of central diabetes insipidusCauses of central diabetes insipidusCauses of central diabetes insipidus Congenital central diabetes insipidus Congenital cytomegalovirus infection Familial (autosomal dominant) Familial hypopituitarism Septo-optic dysplasia Acquired central diabetes insipidus Autoimmune Lymphocytic hypophysitis Granulomatous Bronchocentric granulomatosis Histiocytosis Sarcoidosis Wegener's granulomatosis Idiopathic Infections Bacterial meningitis Blastomycosis Syphilis Tuberculosis Viral encephalitis Ischemic Brain death Sheehan's syndrome Neoplastic Craniopharyngioma Lymphoma Meningioma Metastatic tumors Pineal tumors Pituitary tumors Postsurgical Trauma

Agents that alter vasopressin releaseAgents that alter vasopressin releaseAgents that alter vasopressin release Enhancing Agents Acetylcholine Anesthetic agents Angiotensin II Barbiturates ß-Adrenergic agents Carbamazepine* Clofibrate* Cyclophosphamide* Histamine Hypercapnia Hypoxia Metoclopramide Morphine and narcotic analogues Nicotine Prostaglandin E2 Suppressing Agents à-Adrenergic agents Alcohol Atrial natriuretic peptide Phenytoin Vincristine* *Commonly associated with syndrome of antidiuretic hormone.

Treatment of diabetes insipidusTreatment of diabetes insipidusTreatment for Central Diabetes Insipidus Type of Therapy Dose Route of Administration Duration of Action, h Usage/Comments Arginine vasopressin replacement:

Aqueous vasopressin 5-10 U SC, IM 4-6 Useful for diagnostic testing; acute management after trauma or surgery

Vasopressin tannate in oil 1.5-5 U IM 24-72 Long-term management failures can be due to improper mixing of emulsion

Side effects include smooth muscle contraction, angina, abdominal cramps

Lysine vasopressin 5-10 U Nasal spray 4-6 Short-acting, relatively nonirritating

Desmopressin 5-20 µg Nasal drops 12-24 Preferred drug 10-40 µg Nasal spray 12-24 Few side effects 1-4 µg SC 12-24 0.1-0.8 mg PO 12 Adjunctive therapy: Thiazide diuretics, eg, hydrochlorothiazide

50-100 mg/d PO 12-24 Also useful in nephrogenic diabetes insipidus Sodium loading diminishes effectiveness

Chlorpropamide 250-750 mg/d PO 24-36 Useful only in partial central diabetes insipidus Hypoglycemia is not uncommon

Clofibrate 250-500 mg every 6-8 h PO 6-8 Useful only in partial central diabetes insipidus Frequent side effects

SC—subcutaneously; IM—intramuscularly; PO—orally.

Diabetes insipidus in pregnancy Diabetes insipidus in pregnancy associated with abnormally high associated with abnormally high

circulating vasopressinase circulating vasopressinase activityactivity

J. A. Durr, J. G. Hoggard, J. M. J. A. Durr, J. G. Hoggard, J. M. Hunt, and R. W. Schrier Hunt, and R. W. Schrier

NEJM 1987 316:1070

Aggravation of subclinical diabetes Aggravation of subclinical diabetes insipidus during pregnancyinsipidus during pregnancy

Y Iwasaki, Y Oiso, K Kondo, S Takagi, K Y Iwasaki, Y Oiso, K Kondo, S Takagi, K Takatsuki, H Hasegawa, K Ishikawa, Y Takatsuki, H Hasegawa, K Ishikawa, Y

Fujimura, S Kazeto, and A TomitaFujimura, S Kazeto, and A Tomita

NEJM 1991 324:522

TERMINATION OF DEHYDRATION TERMINATION OF DEHYDRATION TESTTEST

5% Loss of body wt5% Loss of body wt Posm >295-300Posm >295-300 Na >150Na >150 Uosm >600Uosm >600 SG >1.020SG >1.020

PT JLPT JL

TIMETIME VOLVOL uSGuSG uOSMuOSM NaNa pOSMpOSM WTWT7 PM7 PM88 700700 10051005 163163 138138 283283 82.582.599 200200 10051005 163163 138138 282282 82.282.21010 200200 10381038 302302 138138 81.781.71111 6060 10131013 440440 138138 81.281.21212 5050 10111011 387387 137137 81.281.21 AM1 AM 30302:302:30 150150 10111011 378378 139139 278278 81.381.3