DIABETES INSIPIDUS

Dr. Abdelaziz ElaminMD, PhD, FRCPCHProfessor of Child Healthconsultant pediatric

endocrinologistSultan Qaboos UniversityMuscat, Oman.azizmin@hotmail.com

DIABETES INSIPIDUS

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.

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.

DIABETES INSIPIDUS /2

Nephrogenic DI results when the renal tubules of the kidneys fail to respond to circulating ADH.

The resulting renal concentration

defect leads to the loss of large volumes of dilute urine. This causes cellular and extracellular dehydration and hypernatremia.

THE POSTERIOR PITUITARY

Is composed of nerve fibers that have their cell bodies in the supraoptic & paraventricular nuclei of the hypothalamus.

The neurosecretory cells in these nuclei synthesize Oxytocin & Vasopressin which pass down the nerve fibres to be stored in & released from the posterior pituitary.

REGULATION OF ADH SECRETION

ADH RELEASE IS STIMULATED BY:

A PLASMA OSMOLALITY >280 mOsm/l A FALL IN PLASMA VOLUME EMOTIONAL FACTORS & STRESS SLEEP OTHER FACTORS

Other ADH Stimulants

CHOLINERGIC STIMULATION a-ADRENERGIC STIMULATIONANGIOTENSIN IIPROSTAGLANDIN EOPIATESNICOTINEHISTAMINEETHERPHENOBARBITONE

ADH SECRETION IS INHIBITED BY:

ALCOHOL

OROPHARYNGEAL WATER REFLEX

b-DRENERGIC STIMULANTS

ATRIAL NATRIURETIC FACTOR (ANF)

PHENYTOIN

ADH

THE SUPRAOPTIC NUCLEUS (SON) IS RESPONSIBLE PREDOMINANTLY FOR THE SYNTHESIS OF VASOPRESSIN WHICH IS THE ADH.

THE CLOSE STRUCTURAL SIMILARITY OF VASOPRESSIN & OXYTOCIN EXPLAINS THE OVERLAP OF THEIR BIOLOGICAL ACTIONS.

ADH (2)

ADH IS AN OCTAPEPTIDE LIKE OXYTOCIN.

THE ARGININE VASOPRESSIN IS ADH IN MAN AND OTHER MAMMALS APART FROM THE PIG & THE HIPPOPOTAMUS WHERE LYSINE VASOPRESSIN IS THE ADH.

FUNCTION OF ADH

PRIMARY EFFECT OF ADH IS ON THE CELLS OF THE DISTAL TUBULES & COLLECTING DUCTS OF THE KIDNEY PROMOTING REABSORPTION OF WATER.

THIS ACTION IS MEDIATED VIA V2-RECEPTORS

THROUGH ACTIVATION OF cAMP AND FORMATION OF A SPECIFIC PROTEIN KNOWN AS AQUAPORIN.

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

Actions of ADH (3)

DURING HYPOVOLEMIA HIGH PLASMA LEVELS OF AVP HELP MAINTAIN TISSUE PERFUSSION.

A LESSER SECONDARY EFFECT THAT IS MEDIATED VIA V2 NON-RENAL RECEPTORS IS STIMULATION OF SYNTHESIS & RELEASE OF FACTOR VIII & VON WILLEBRAND FACTOR.

CAUSES OF CENTRAL DI

IDIOPATHIC (30% OF CASES) SUPRASELLAR TUMOURS (30% OF CASES) INFECTIONS (ENCEPHALITIS, TB, etc) NON-INFECTIOUS GRANULOMA (SARCOID,

HAND-SCHULLER CHRISTIAN DISEASE TRAUMA OR SKULL SURGERY LEUKAEMIA

CAUSES OF CENTRAL DI (2)

AUTOIMMUNE ASSOCIATED WITH THYROIDITIS

FAMILIAL: 2 TYPES AD & X-LINKED

INHERITANCE

WOLFRAM SYNDROME (ALSO KNOWN AS

DIDMOAD SYNDROME) CHARACTERIZED BY DI,

DM, NERVE DEAFNESS AND OPTIC ATROPHY.

CAUSES OF NEPHROGENIC DI

PRIMARY FAMILIAL: X-LINKED RECESSIVE THAT IS SEVERE IN BOYS & MILD IN GIRLS

SECONDARY TO: CHRONIC PYELONEPHRITIS HYPOKALEMIA HYPERCALCEMIA SICKLE CELL DISEASE PROTEIN DEPRIVATION

CAUSES OF NEPHROGENIC DI/2

SECONDARY CAUSES continued: AMYLOIDOSIS

OTHER RENAL DISEASES (chronic renal failure,

obstructive uropathy, polycystic disease)

SJOGREN SYNDROME

DRUGS (Lithium, Colchicine, Fluoride,

Cidofovir, Demeclocycline, Methoyflurane)

CLINICAL FEATURES

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

COMPLICATIONS

HYPERNATREMIC DEHYDRATION &

ITS NEUROLOGICAL SEQUELEA

GROWTH RETARDATION

HYDRONEPHROSIS (DUE TO

EXCESSIVE URINE OUTPUT)

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

DIAGNOSTIC WORKUP (2)

URINALYSIS & MICROSCOPY TOGETHER WITH PLASMA ELECTROLYTES HELP EXCLUDE MOST OF THE CAUSES OF POLYURIA

IN A NORMAL WELL HYDRATED SUBJECT PLASMA OSMOLALITY IS <290 mOsml/l AND URINE OSMOLALITY IS 300-450 mOsmol/l

DIAGNOSTIC WORKUP (3)

IN PATIENTS WITH DI & FREE EXCESS TO WATER PLASMA OSMOLALITY IS >295 mOsmol/l & URINE OSOLALITY IS 50-150 mOsmol/l.

IN PATIENTS WITH DI & FREE EXCESS TO WATER PLASMA OSMOLALITY IS >295 mOsmol/l & URINE OSOLALITY IS 50-150 mOsmol/l.

WATER DEPRIVATION TEST

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

WATER DEPRIVATION TEST (2)

SHOULD BE DONE IN THE MORNING UNDER OBSERVATION

8 HOURS FAST IS ENOUGH FOR CHILDREN WEIGH THE CHILD HOURLY AND MEASURE

PLASMA & URINE OSMOLALITY EVERY 2 HOURS IN NORMAL SUBJECTS PLASMA OSMOLALITY

HARDLY RISES (< 300) BUT THE URINE OUTPUT IS REDUCED & ITS OSMOLALITY RISES (800-1200)

WATER DEPRIVATION TEST (3)

PATIENTS WITH PRIMARY POLYDIPSIA START WITH LOW NORMAL PLASMA OSMOLALITY (280) BUT URINE/PLASMA OSMOLALITY RATIO RISES TO >2 AFTER DEHYDRATION.

IN PATIENTS WITH DI THE PLASMA BUT NOT THE URINE OSMOLALITY RISES AND U/P OSMOLALITY RATIO REMAINS < 1.5

WATER DEPRIVATION TEST (4)

AT THE END OF THE TEST, ADH IS GIVEN (20 mg DDAVP INTRNASALLY OR 2 mg I.M.) AND FLUID INTAKE ALLOWED.

CONCENTRATION OF THE DILUTE URINE

CONFIRMS CENTRAL DI AND FAILURE SUGGEST NEPHROGENIC CAUSES

TREATMENT

DESMOPRESSIN (DDAVP) A SYNTHETIC ANALOG IS SUPERIOR TO NATIVE AVP BECAUSE:

IT HAS LONGER DURATION OF ACTION (8-10 h vs 2-3 h)

MORE POTENT ITS ANTIDIURETIC ACTIVITY IS 3000

TIMES GREATER THAN ITS PRESSOR ACTIVITY

DDAVP

USUALLY GIVEN INTRANASALLY BUT CAN BE GIVEN ORALLY OR I.M. FOR COMATOSE PATIENTS OR DURING SURGERY.

DDAVP CAN ALSO BE USED IN MILD HAEMOPHILIA OR VON WILLEBRAND DISEASE AND AS TREATMENT FOR NOCTURNAL ENURESIS IN CHILDREN

TREATMENT OF NEPHROGENIC DI

PROVISION OF ADEQUATE FLUIDS & CALORIE

LOW SODIUM DIET DIURETICS HIGH DOSE OF DDAVP CORRECTION OF UNDERLYING CAUSE DRUGS (Indomethacin, Chlorprooramide,

Clofibrate & Carbamazepine)