Diabetes Insipidus

Diabetes insipidus:

• • Diabetes insipidus (DI) is caused by decreased secretion or action of arginine vasopressin (AVP), resulting in the production of abnormally large volumes of dilute urine.

    • • 24-hour urine volume is > 50 mL/kg body weight.

      • Urine osmolarity is < 300 mosmol/L.

      • Hypernatremia

  • Neurohypophyseal DI is caused by deficient AVP secretion from the neurohypophysis (posterior pituitary).

  • Nephrogenic DI is caused by defective AVP action to reabsorb water via the renal collecting tubules.

Risk factors:

Neurohypophyseal DI

• • Head trauma (closed and penetrating)

  • Disorders associated with destruction of the hypothalamus

    • • Neoplasms

      • Granulomatous disorders

      • Infections

      • Inflammatory processes

      • Exposure to chemical toxins

  • Pituitary surgery

  • Genetic disorders including mutations in the AVP gene

  • Pregnancy (vasopressinase)

  • Presence of congenital malformations

Nephrogenic DI

• • Drugs

  • Metabolic

    • • Hypercalcemia/hypercalciuria

      • Hypokalemia

  • Obstruction of ureter or urethra

  • Vascular insufficiency

  • Genetic disorders

    • • AVP receptor mutations

      • Aquaporin-2 mutations

Primary polydipsia

• • Psychiatric disorders

    • • Schizophrenia

      • Obsessive-compulsive disorder

Etiology

Neurohypophyseal DI

• • All forms are associated with deficient secretion of AVP resulting from agenesis or irreversible destruction of the neurohypophysis.

Genetic

• • Autosomal dominant

    • • Most common familial form of neurohypophyseal DI

      • Caused by diverse monoallelic mutations in the AVP-neurophysin gene, which lead to cellular toxicity and degeneration of AVP-producing neurons

      • AVP deficiency develops after birth and progresses from partial to severe.

  • Autosomal recessive

    • • Rare familial form of neurohypophyseal DI

      • Caused by inactivating bi-allelic mutations in AVP-neurophysin gene, resulting in the production of mutant AVP with little antidiuretic effect

  • Autosomal recessive associated with Wolfram syndrome (see Associated Conditions)

  • X-linked recessive

    • • Rare familial form of neurohypophyseal DI

      • Linked to an unidentified gene on chromosome Xq28

      • Results in progressive postnatal loss of AVP secretory capacity

  • Deletion of chromosome 7q

Acquired

• • Head trauma (closed and penetrating)

  • Neoplasms

    • • Primary

        • • Craniopharyngioma

          • Pituitary adenoma (suprasellar)

          • Dysgerminoma

          • Meningioma

      • Metastatic (lung, breast)

      • Hematologic (lymphoma, leukemia)

  • Granulomas

    • • Neurosarcoidosis

      • Histiocytosis

      • Xanthoma disseminatum

  • Infections

    • • Chronic meningitis

      • Viral encephalitis

      • Toxoplasmosis

  • Inflammatory processes

    • • Lymphocytic infundibuloneurohypophysitis

      • Wegener’s granulomatosis

      • Lupus erythematosus

      • Scleroderma

  • Chemical toxins

    • • Tetrodotoxin

      • Snake venom

  • Vascular

    • • Sheehan’s syndrome

      • Aneurysm (internal carotid)

      • Aortocoronary bypass

      • Hypoxic encephalopathy

  • Pregnancy (vasopressinase)

Congenital malformations

• • Septo-optic dysplasia

  • Midline craniofacial defects

  • Holoprosencephaly

  • Hypogenesis

Idiopathic

• • Approximately 50% of patients

Nephrogenic DI

• • All forms are associated with impaired action of AVP.

  • Genetic

    • • X-linked recessive

        • • Most common familial form of nephrogenic DI

          • Men tend to have marked polyuria; some female carriers can be mildly symptomatic.

          • Caused by inactivating mutations in the AVP receptor-2 gene

          • Present from birth

      • Autosomal dominant or recessive

        • • Rare familial forms of nephrogenic DI

          • Caused by inactivating monoallelic or bi-allelic mutations in the aquaporin-2 gene, which lead to impaired trafficking of water channels

  • Acquired

    • • Drugs

• • • • • Lithium

        • Demeclocycline

        • Methoxyflurane

        • Amphotericin B

        • Aminoglycosides

        • Cisplatin

        • Rifampin

        • Foscarnet

• • • • Metabolic

        • • Hypercalcemia/hypercalciuria

          • Hypokalemia

      • Obstruction of ureter or urethra

      • Vascular

        • • Sickle-cell disease or trait

          • Ischemia (acute tubular necrosis)

      • Granuloma (neurosarcoid)

      • Neoplasm

        • • Sarcoma

      • Infiltration

        • • Amyloidosis

      • Pregnancy

  • Idiopathic

Primary polydipsia

• • All forms are associated with inhibition of AVP secretion due to excessive intake of fluids.

    • • Excessive intake of fluids slightly increases body water, thereby reducing plasma osmolarity, AVP secretion, and urinary concentration.

      • The latter results in a compensatory increase in urinary free-water excretion that varies in direct proportion to intake.

  • Psychogenic

    • • Due to psychosis, not associated with thirst

      • Schizophrenia

      • Obsessive-compulsive disorder

  • Dipsogenic

    • • Associated with an inappropriate increase in thirst due to reduction in the set-point of the osmoregulatory mechanism

      • May occur in association with multifocal diseases of the brain, such as neurosarcoid, tuberculous meningitis, or multiple sclerosis, but is often idiopathic

  • Iatrogenic

    • • Results from recommendations of health professionals or the popular media to increase fluid intake for its presumed preventive or therapeutic benefits for other disorders

Symptoms & Signs

• • Polyuria

  • Urinary frequency

  • Enuresis

  • Nocturia

  • Polydipsia (increase in fluid intake)

  • Thirst

  • Mild daytime fatigue/somnolence, as a consequence of polyuria

  • Signs of dehydration (rare)

    • Only if fluid intake is impaired

Treatment:

Diabetes insipidus

- history of DI prior to most recent surgery: has been between DI/SIADH (due to surg/cell death of paraventricular nucleus?)

-Continue DDAVP nasally 10 mcg total QHS (1 puff (10 mcg) in one nostril) -Continue DDAVP nasally 20 mcg total QAM (1 puff (10 mcg) in EACH nostril)

-DDAVP add'l 10mcg for Na > 140, hold dose for <136.

-Urine output > 300 cc/hr for three hours give an extra puff nasally (10 mcg) in one nostril

- monitor Na q12. Endo and NSG collabing protocol for floor to follow, we understand a goal of UOP <300/hr, Na~140

- Strict I/Os.

- Urine Na, osm vs serum obtained for DI vs SIADH = No SIADH.

Diagnostic Approach

• • Historical features

    • • Sellar masses or surgery

      • Diseases associated with DI (e.g., granulomatous disorders)

      • Family history suggestive of genetic cause

      • Medications associated with neurohypophyseal or nephrogenic DI

  • Measurement of 24-hour urine output

    • • Diagnosis of polyuria is confirmed if output is > 50 mL/kg daily (>3,500 mL in a 70-kg man).

      • Urine osmolarity < 300 mosmol/L indicates a water diuresis and should be further evaluated with fluid deprivation test.

      • Urine osmolarity > 300 mosmol/L indicates that polyuria is due to a solute diuresis and should be followed by evaluation for test for diabetes mellitus or other cause of excessive solute excretion.

  • Fluid deprivation test (see Diagnostic Procedures)

    • • Physiologic principal: Dehydration causes elevation of plasma osmolality which stimulates AVP secretion, causing concentration of urine.

      • Patients with excessive thirst will concentrate urine; patients with DI will not.

      • Test differentiates patients with DI from patients with primary polydipsia.

      • Requires experienced specialist in a monitored setting

• Desmopressin (1-desamino-8-D-arginine vasopressin [DDAVP]) challenge (second part of fluid deprivation test)

  • • Physiologic principal: DDAVP causes urine concentration.

    • Patients with neurohypophyseal DI will concentrate urine by at least 50%, after receipt of DDAVP; patients with nephrogenic DI will not.

    • The test differentiates neurohypophyseal and nephrogenic DI.

• • The differential diagnosis of DI may also be facilitated by MRI of the pituitary and hypothalamus.

Laboratory Tests

• • 24-hour urine output

    • • Measure volume, osmolarity, and creatinine content.

      • Polyuria if > 50 mL/kg daily (>3,500 mL in a 70-kg man)

  • Urine osmolarity

    • • Osmolarity < 300 mosmol/L may be indicative of DI.

      • Osmolarity ≥ 300 mosmol/L usually excludes DI.

      • Urine osmolality and the response of dDAVP. Small volume of concentrated urine (Uosm >800 mOsm/L). Submaximal urine osmolalilty (<800 mOsm/L) suggests a defect in renal water conservation.

      • Urine Osm <300 mOsm in the setting of hypernatremia suggest complete forms of CDI and NDI.

      • Urine osm 300 - 800 mOsm/L can occur from partial forms of DI as well as osmotic diuresis. The two can be differentiated by quantifying the daily solute excretion (estimated by the urine osmolality x urine volume in 24 hrs). A daily solute excretion >900 mOsm defines osmotic diuresis (glucosuria, mannitol, ▲ BUN, high solute loads).

Imaging

• • MRI of pituitary and hypothalamus

    • • "Bright spot" refers to the hyperintense signal in T1-weighted mid-sagittal images in the region of the posterior pituitary.

      • The MRI bright spot is most useful for excluding a diagnosis of neurohypophyseal DI.

        • • It is absent or abnormally small in most patients with neurohypophyseal DI; therefore, a normal bright spot usually excludes pituitary DI.

          • Present in 80–90% with primary polydipsia

          • Should be performed in conjunction with other tests