DIABETES INSIPIDUS

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DIABETES INSIPIDUS

• Dr. Abdelaziz Elamin
• MD, PhD, FRCPCH
• Professor of Child Health
• consultant pediatric endocrinologist
• Sultan Qaboos University
• Muscat, Oman.
• azizmin_at_hotmail.com

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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.

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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.

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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.

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REGULATION OF ADH SECRETION

• ADH RELEASE IS STIMULATED BY
• A PLASMA OSMOLALITY gt280 mOsm/l
• A FALL IN PLASMA VOLUME
• EMOTIONAL FACTORS STRESS
• SLEEP
• OTHER FACTORS

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Other ADH Stimulants

• CHOLINERGIC STIMULATION
• a-ADRENERGIC STIMULATION
• ANGIOTENSIN II
• PROSTAGLANDIN E
• OPIATES
• NICOTINE
• HISTAMINE
• ETHER
• PHENOBARBITONE

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ADH SECRETION IS INHIBITED BY

• ALCOHOL
• OROPHARYNGEAL WATER REFLEX
• b-DRENERGIC STIMULANTS
• ATRIAL NATRIURETIC FACTOR (ANF)
• PHENYTOIN

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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.

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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.

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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.

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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

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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.

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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

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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.

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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

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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)

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CLINICAL FEATURES

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

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COMPLICATIONS

• HYPERNATREMIC DEHYDRATION ITS NEUROLOGICAL
  SEQUELEA
• GROWTH RETARDATION
• HYDRONEPHROSIS (DUE TO EXCESSIVE URINE OUTPUT)

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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

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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 lt290 mOsml/l AND URINE OSMOLALITY
  IS 300-450 mOsmol/l

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DIAGNOSTIC WORKUP (3)

• IN PATIENTS WITH DI FREE EXCESS TO WATER PLASMA
  OSMOLALITY IS gt295 mOsmol/l URINE OSOLALITY IS
  50-150 mOsmol/l.
• IN PATIENTS WITH DI FREE EXCESS TO WATER PLASMA
  OSMOLALITY IS gt295 mOsmol/l URINE OSOLALITY IS
  50-150 mOsmol/l.

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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

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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
  (lt 300) BUT THE URINE OUTPUT IS REDUCED ITS
  OSMOLALITY RISES (800-1200)

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WATER DEPRIVATION TEST (3)

• PATIENTS WITH PRIMARY POLYDIPSIA START WITH LOW
  NORMAL PLASMA OSMOLALITY (280) BUT URINE/PLASMA
  OSMOLALITY RATIO RISES TO gt2 AFTER DEHYDRATION.
• IN PATIENTS WITH DI THE PLASMA BUT NOT THE URINE
  OSMOLALITY RISES AND U/P OSMOLALITY RATIO REMAINS
  lt 1.5

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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

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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

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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

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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)