Vasopressin Receptor Mutations in Nephrogenic Diabetes Insipidus
Diabetes insipidus gk
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Transcript of Diabetes insipidus gk
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DIABETES INSIPIDUS
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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 >280 mOsm/l
A FALL IN PLASMA VOLUME EMOTIONAL FACTORS & STRESS SLEEP OTHER FACTORS
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Other ADH Stimulants
CHOLINERGIC STIMULATION a-ADRENERGIC STIMULATIONANGIOTENSIN IIPROSTAGLANDIN EOPIATESNICOTINEHISTAMINEETHERPHENOBARBITONE
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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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Antidiuretic effect of arginine vasopressin (AVP) in the regulation of urine volume
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Etiology
Deficient secretion of AVP can be primary or secondary. The primary form usually results from agenesis or irreversible destruction of the neurohypophysis and is referred to variously as neurohypophyseal DI, pituitary DI, or central DI. Secondary deficiencies of AVP result from inhibition of secretion by excessive intake of fluids. They are referred to as primary polydipsia Primary deficiencies in the antidiuretic action of AVP result in nephrogenic DI
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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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Primary polydipsia
can be divided into three subcategories. One of them, dipsogenic DI, is characterized by inappropriate thirst caused by a reduction in the set of the osmoregulatory mechanism. It sometimes occurs in association with multifocal diseases of the brain such as neurosarcoid, tuberculous meningitis, and multiple sclerosis but is often idiopathic. The second subtype, psychogenic polydipsia, is not associated with thirst, and the polydipsia seems to be a feature of psychosis or obsessive compulsive disorder. The third subtype, iatrogenic polydipsia, results from recommendations to increase fluid intake for its presumed health benefits.
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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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Differential Diagnosis
When symptoms of urinary frequency, enuresis, nocturia, and/or persistent thirst are present, the possibility of DI should be evaluated after excluding glucosuria by collecting a 24-hour urine on ad libitum fluid intake. If the volume exceeds 50 mL/kg per day (3500 mL in a 70-kg male) and the osmolarity is >300 mosmol/L, DI is confirmed and the patient should be evaluated further to determine the type.
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Differential Diagnosis
In differentiating among the various types of DI, the history alone may be sufficient if it reveals a likely antecedent such as pituitary surgery. Usually, however, that type of indicator is absent, ambiguous, or misleading and other approaches are needed. Except in the rare patient with hypertonic dehydration under basal conditions, differentiation should begin with a fluid deprivation test.
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Treatment
Desmopressin can be given by IV or SC injection, nasal inhalation, or oral tablet. The doses required to control pituitary DI completely vary widely, depending on the patient and the route of administration. However, they usually range from 1–2 g qd or bid by injection, 10–20 g bid or tid by nasal spray, or 100–400 g bid or tid orally. The onset of action is rapid, ranging from as little as 15 minutes after injection to 60 minutes after oral administration.