1. DIABETES INSIPIDUS Dr. Abdelaziz Elamin MD, PhD, FRCPCH Professor of Child Health consultant pediatric endocrinologist Sultan Qaboos University Muscat, Oman. azizmin@hotmail.com

2. DIABETES INSIPIDUS l DI is a disorder resulting from deficiency of anti-diuretic hormone (ADH) or its action and is characterized by the passage of copious amounts of dilute urine. l It must be differentiated from other polyuric states such as primary polydipsia & osmotic duiresis. Central DI is due to failure of the pituitary gland to secrete adequate ADH.

3. DIABETES INSIPIDUS /2 l Nephrogenic DI results when the renal tubules of the kidneys fail to respond to circulating ADH. l The resulting renal concentration defect leads to the loss of large volumes of dilute urine. This causes cellular and extracellular dehydration and hypernatremia.

4. THE POSTERIOR PITUITARY l Is composed of nerve fibers that have their cell bodies in the supraoptic & paraventricular nuclei of the hypothalamus. l The neurosecretory cells in these nuclei synthesize Oxytocin & Vasopressin which pass down the nerve fibres to be stored in & released from the posterior pituitary.

5. REGULATION OF ADH SECRETION ADH RELEASE IS STIMULATED BY: l A PLASMA OSMOLALITY >280 mOsm/l l A FALL IN PLASMA VOLUME l EMOTIONAL FACTORS & STRESS l SLEEP l OTHER FACTORS

6. Other ADH Stimulants  CHOLINERGIC STIMULATION  a-ADRENERGIC STIMULATION  ANGIOTENSIN II  PROSTAGLANDIN E  OPIATES  NICOTINE  HISTAMINE  ETHER  PHENOBARBITONE

7. ADH SECRETION IS INHIBITED BY: l ALCOHOL l OROPHARYNGEAL WATER REFLEX l b-DRENERGIC STIMULANTS l ATRIAL NATRIURETIC FACTOR (ANF) l PHENYTOIN

8. ADH l THE SUPRAOPTIC NUCLEUS (SON) IS RESPONSIBLE PREDOMINANTLY FOR THE SYNTHESIS OF VASOPRESSIN WHICH IS THE ADH. l THE CLOSE STRUCTURAL SIMILARITY OF VASOPRESSIN & OXYTOCIN EXPLAINS THE OVERLAP OF THEIR BIOLOGICAL ACTIONS.

9. ADH (2) l ADH IS AN OCTAPEPTIDE LIKE OXYTOCIN. l THE ARGININE VASOPRESSIN IS ADH IN MAN AND OTHER MAMMALS APART FROM THE PIG & THE HIPPOPOTAMUS WHERE LYSINE VASOPRESSIN IS THE ADH.

10. FUNCTION OF ADH l PRIMARY EFFECT OF ADH IS ON THE CELLS OF THE DISTAL TUBULES & COLLECTING DUCTS OF THE KIDNEY PROMOTING REABSORPTION OF WATER. l THIS ACTION IS MEDIATED VIA V2-RECEPTORS THROUGH ACTIVATION OF cAMP AND FORMATION OF A SPECIFIC PROTEIN KNOWN AS AQUAPORIN.

11. Actions of ADH (2)  Beside water, AVP enhances reabsorption of urea increasing tonicity of the renal medulla allowing more water to be re-absorbed.  Acting on v1-receptors in peripheral vessels AVP causes vaso-constriction &  BP. Normally this is balanced by its inhibitory effect on sympathetic cardiac stimuli causing bradycardia

12. Actions of ADH (3) l DURING HYPOVOLEMIA HIGH PLASMA LEVELS OF AVP HELP MAINTAIN TISSUE PERFUSSION. l A LESSER SECONDARY EFFECT THAT IS MEDIATED VIA V2 NON-RENAL RECEPTORS IS STIMULATION OF SYNTHESIS & RELEASE OF FACTOR VIII & VON WILLEBRAND FACTOR.

13. CAUSES OF CENTRAL DI l IDIOPATHIC (30% OF CASES) l SUPRASELLAR TUMOURS (30% OF CASES) l INFECTIONS (ENCEPHALITIS, TB, etc) l NON-INFECTIOUS GRANULOMA (SARCOID, HAND-SCHULLER CHRISTIAN DISEASE l TRAUMA OR SKULL SURGERY l LEUKAEMIA

14. CAUSES OF CENTRAL DI (2) l AUTOIMMUNE ASSOCIATED WITH THYROIDITIS l FAMILIAL: 2 TYPES AD & X-LINKED INHERITANCE l WOLFRAM SYNDROME (ALSO KNOWN AS DIDMOAD SYNDROME) CHARACTERIZED BY DI, DM, NERVE DEAFNESS AND OPTIC ATROPHY.

15. CAUSES OF NEPHROGENIC DI PRIMARY FAMILIAL: X-LINKED RECESSIVE THAT IS SEVERE IN BOYS & MILD IN GIRLS l SECONDARY TO: l CHRONIC PYELONEPHRITIS l HYPOKALEMIA l HYPERCALCEMIA l SICKLE CELL DISEASE l PROTEIN DEPRIVATION

16. CAUSES OF NEPHROGENIC DI/2 l SECONDARY CAUSES continued: l AMYLOIDOSIS l OTHER RENAL DISEASES (chronic renal failure, obstructive uropathy, polycystic disease) l SJOGREN SYNDROME l DRUGS (Lithium, Colchicine, Fluoride, Cidofovir, Demeclocycline, Methoyflurane)

17. CLINICAL FEATURES l POLYURIA, POLYDIPSIA & THIRST l NOCTURIA OR NOCTURNAL ENURESIS l HYPERNATREMIC DEHYDRATION l ANOREXIA, CONSTIPATION & FTT l HYPERTHERMIA & LACK OF SWEATING l SYMPTOMS OF UNDERLYING CAUSE

18. COMPLICATIONS l HYPERNATREMIC DEHYDRATION & ITS NEUROLOGICAL SEQUELEA l GROWTH RETARDATION l HYDRONEPHROSIS (DUE TO EXCESSIVE URINE OUTPUT)

19. DIAGNOSTIC WORKUP CAREFUL HISTORY & EXAMINATION DOCUMENT PRESENCE OF POLYURIA (USUALLY 4-15 L/24h)  PRACTICALLY SMILTANEOUS MEASUREMENT OF PLASMA & URINE OSMOLALTY ESTABLISH THE DIAGNOSIS IN MOST CHILDREN WITH SEVERE DI MAKING A WATER DEPRIVATION TEST UNNECESSARY

20. DIAGNOSTIC WORKUP (2) l URINALYSIS & MICROSCOPY TOGETHER WITH PLASMA ELECTROLYTES HELP EXCLUDE MOST OF THE CAUSES OF POLYURIA l IN A NORMAL WELL HYDRATED SUBJECT PLASMA OSMOLALITY IS <290 mOsml/l AND URINE OSMOLALITY IS 300-450 mOsmol/l

21. DIAGNOSTIC WORKUP (3) l IN PATIENTS WITH DI & FREE EXCESS TO WATER PLASMA OSMOLALITY IS >295 mOsmol/l & URINE OSOLALITY IS 50-150 mOsmol/l.

22. WATER DEPRIVATION TEST l WATER DEPRIVATION TEST IS NEEDED FOR PATIENTS WITH PARTIAL AVP DEFICIENCY & ALSO TO DIFFERENTIATE DI FROM PRIMARY POLYDIPSIA WHICH IS VERY RARE IN CHILDREN

23. WATER DEPRIVATION TEST (2) l SHOULD BE DONE IN THE MORNING UNDER OBSERVATION l 8 HOURS FAST IS ENOUGH FOR CHILDREN l WEIGH THE CHILD HOURLY AND MEASURE PLASMA & URINE OSMOLALITY EVERY 2 HOURS l IN NORMAL SUBJECTS PLASMA OSMOLALITY HARDLY RISES (< 300) BUT THE URINE OUTPUT IS REDUCED & ITS OSMOLALITY RISES (800-1200)

24. WATER DEPRIVATION TEST (3) l PATIENTS WITH PRIMARY POLYDIPSIA START WITH LOW NORMAL PLASMA OSMOLALITY (280) BUT URINE/PLASMA OSMOLALITY RATIO RISES TO >2 AFTER DEHYDRATION. l IN PATIENTS WITH DI THE PLASMA BUT NOT THE URINE OSMOLALITY RISES AND U/P OSMOLALITY RATIO REMAINS < 1.5

25. WATER DEPRIVATION TEST (4) l AT THE END OF THE TEST, ADH IS GIVEN (20 mg DDAVP INTRNASALLY OR 2 mg I.M.) AND FLUID INTAKE ALLOWED. l CONCENTRATION OF THE DILUTE URINE CONFIRMS CENTRAL DI AND FAILURE SUGGEST NEPHROGENIC CAUSES

26. TREATMENT l DESMOPRESSIN (DDAVP) A SYNTHETIC ANALOG IS SUPERIOR TO NATIVE AVP BECAUSE: l IT HAS LONGER DURATION OF ACTION (8- 10 h vs 2-3 h) l MORE POTENT l ITS ANTIDIURETIC ACTIVITY IS 3000 TIMES GREATER THAN ITS PRESSOR ACTIVITY

27. DDAVP l USUALLY GIVEN INTRANASALLY BUT CAN BE GIVEN ORALLY OR I.M. FOR COMATOSE PATIENTS OR DURING SURGERY. l DDAVP CAN ALSO BE USED IN MILD HAEMOPHILIA OR VON WILLEBRAND DISEASE AND AS TREATMENT FOR NOCTURNAL ENURESIS IN CHILDREN

28. TREATMENT OF NEPHROGENIC DI l PROVISION OF ADEQUATE FLUIDS & CALORIE l LOW SODIUM DIET l DIURETICS l HIGH DOSE OF DDAVP l CORRECTION OF UNDERLYING CAUSE DRUGS (Indomethacin, Chlorprooramide, Clofibrate & Carbamazepine)