Central Diabetes Insipidus

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Central Diabetes Insipidus

• Jennifer Pagliei
• September 17, 2007

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Introduction

• Central diabetes insipidus (CDI) results from any
  condition that impairs the synthesis, transport,
  or release of antidiuretic hormone (ADH), also
  know as arginine vasopressin (AVP).
• It occurs equally in both sexes.
• It effects all ages.
• The complete form is less common than the partial
  form.

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Introduction

• ADH is produced in the hypothalamus and travels
  along nerve fibers to the posterior pituitary,
  where it is stored and released.
• ADH promotes reabsorption of water in the
  collecting duct of nephrons.
• Increased plasma osmolality stimulates release of
  ADH in normal people.
• Patients with complete or partial CDI secrete
  lower than normal levels of plasma ADH in
  response to elevated plasma osmolality.

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Introduction

• In patients with CDI, lack of water reabsorption
  in the collecting ducts of the kidneys due to
  decreased secretion of ADH results in polyuria.
• In most patients, the degree of polyuria is
  primarily determined by the degree of ADH
  deficiency.
• The urine output can range from 3 L/day in mild
  partial DI to over 15 L/day in patients with
  severe disease.
• CDI can be worsened or first diagnosed during
  pregnancy, when ADH catabolism is increased by
  vasopressinases released from the placenta.

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Etiology

• The most common causes of central DI are
• Neurosurgery
• Brain trauma
• Primary or metastatic brain tumors
• Infiltrative diseases
• Idiopathic DI
• Hypoxic or ischemic encephalopathy
• Familial DI
• Radiation to the brain
• Infection such as meningitis or encephalitis
• Cerebral edema
• Intracranial hemorrhage

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Etiology

• Idiopathic DI
• Accounts for 30 to 50 of cases of CDI.
• Is thought to be due to autoimmune destruction of
  the ADH hormone-secreting cells in the
  hypothalamus.
• It is characterized by lymphocytic inflammation
  of the pituitary stalk and posterior pituitary
  that resolves after destruction of the target
  neurons.
• MRI early in the course often reveals thickening
  or enlargement of these structures.

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Etiology

• Familial DI
• Also called familial neurohypophyseal diabetes
  insipidus (FNDI).
• Usually an autosomal dominant disease caused by
  mutations in the ADH gene.
• Patients progressively develop ADH deficiency.
• Clinical and hormonal signs usually do not
  develop until several months or years after
  birth.

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Etiology

• Neurosurgery or Trauma
• CDI can be induced by neurosurgery (usually
  transsphenoidal) or trauma to the hypothalamus or
  posterior pituitary.
• The incidence varies with the extent of injury
• It is 10 to 20 after transsphenoidal removal of
  an adenoma limited to the sella.
• It is as high as 60 to 80 after removal of very
  large tumors.
• MRI of the hypothalamus and pituitary is helpful
  in identifying the anatomical location of
  neuronal damage.
• Low, distal lesions have a higher resolution rate
  than higher, more proximal ones.

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Etiology

• Cancer
• CDI can result from primary or metastatic tumors
  in the brain that involve the hypothalamic-pituita
  ry region.
• CDI resulting from metastatic disease is most
  commonly seen with
• Lung cancer
• Leukemia
• Lymphoma

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Etiology

• Hypoxic or ischemic encephalopathy
• Can lead to diminished ADH release.
• It may occur due to cardiopulmonary arrest or
  cardiogenic shock.
• The severity of resulting CDI varies, ranging
  from mild and asymptomatic to significant
  polyuria.

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Etiology

• Infiltrative Disorders
• The most common example is Langerhans cell
  histiocytosis (aka histiocytosis X or
  eosinophilic granuloma).
• Patients are at very high risk for CDI due to
  hypothalamic-pituitary disease.
• Up to 40 of patients become polyuric within the
  first four years, especially if there is
  multisystem involvement and proptosis.
• Other infiltrative disorders that can cause CDI,
  but rarely do so include
• Wegeners granulomatosis
• Autoimmune lymphocytic hypophysitis

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Etiology

• Acute fatty liver of pregnancy
• Transient CDI has been associated with it but no
  mechanism has been identified.
• Wolfram syndrome (or DIDMOAD syndrome)
• An autosomal recessive disorder with incomplete
  penetrance.
• Characterized by CDI, DM, optic atrophy, and
  deafness.
• CDI is due to loss of ADH-secreting neurons in
  the hypothalamus and impaired processing of ADH
  precursors.

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Symptoms

• The major symptoms of central DI are polyuria and
  polydipsia.
• Polyuria is defined as a urine output of over 3
  L/day in adults.
• Polyuria must be differentiated from frequency
  and nocturia, which are not associated with an
  increase in total urine output.
• The onset of polyuria is usually abrupt in CDI.
• This is in contrast to nephrogenic DI and primary
  polydipsia, in which onset of polyuria is almost
  always gradual.

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Symptoms

• Nocturia is often the first sign of CDI.
• This is because urine is usually most
  concentrated in the morning due to lack of fluid
  ingestion overnight.
• As a result, nocturia is usually the first
  manifestation of a loss of concentrating ability.
• Thus, a relatively dilute urine is excreted, with
  a urine osmolality of less than 200 mOsmol/kg.
• Dry skin and constipation are other symptoms that
  may occur in CDI.

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Diagnosis

• Most patients have a high-normal or only mildly
  elevated plasma sodium concentration, usually
  greater than 142 mEq/L.
• In addition, the plasma osmolality usually
  remains around values only slightly above 290
  mOsm/kg (normal is 280-295 mOsm/kg).
• This occurs because the initial loss of water
  results in concurrent stimulation of thirst,
  which minimizes the degree of net water loss.

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Diagnosis

• Stimulation of thirst does not occur, however,
  when CDI is due to a central lesion that impairs
  thirst causing hypodipsia or adipsia.
• In such cases, the plasma sodium concentration
  can exceed 160 meq/L and the plasma osmolality
  will rise significantly also.
• This also occurs if a patient has no access to
  water.
• Withholding water in patients with CDI can result
  in severe dehydration.

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Diagnosis

• Water restriction test
• Not required for the diagnosis of DI, but is
  helpful in differentiating central DI from
  nephrogenic DI and primary polydipsia.
• Recommended to confirm the diagnosis even if the
  history or plasma sodium concentration appear to
  be helpful.
• Used to raise the plasma osmolality.
• Hypertonic saline (0.05 mL/kg/min for less than 2
  hrs) can be used if the water restriction test is
  inconclusive or cannot be done.

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Water Restriction Test

• In healthy individuals, water deprivation
  increases plasma osmolality, which stimulates
  secretion of ADH by the posterior pituitary.
• This then acts on the kidney to increase urine
  osmolality to 1000 to 1200 mOmol/kg and to
  restore plasma osmolality to normal levels.
• Giving exogenous ADH does not increase urine
  osmolality further because it is already maximal
  in response to an individuals endogenous release
  of ADH.

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Water Restriction Test

• Method
• Water restriction lasts 4 to 18 hours.
• Overnight fluid restriction should be avoided, as
  severe volume depletion and hypernatremia can be
  induced in patients with severe polyuria.
• Measure the urine volume and osmolality every
  hour and serum sodium concentration and
  osmolality every two hours.

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Water Restriction Test

• The test should be continued until one of the
  following occurs
• The urine osmolality reaches a normal value,
  which is above 600 mOsm/kg, indicating that both
  ADH release and effect are intact.
• The urine osmolality is stable on 2 or 3
  successive measurements despite a rising plasma
  osmolality.
• The plasma osmolality exceeds 295 to 300 mOsm/kg.
• In the last two settings, the serum ADH level is
  measured, which is also performed at the start of
  the test, and then exogenous ADH is administered
  (10 microgm of dDAVP nasally or 4 microgm sq).
• Urine osmolality is then measured every 30
  minutes for the next 3 hours.

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Water Restriction Test

• In patients with complete CDI
• Water deprivation increases plasma osmolality but
  urine osmolality remains below 290 mOsm/kg and
  does not increase.
• Urine osmolality will increase by approximately
  200 mOsm/kg in response to exogenous ADH.
• In patients with partial CDI
• Urine osmolality will increase somewhat to 400 to
  500 mOsm/kg during water deprivation, but is
  still well below that of normal people.
• Urine osmolality will increase by approximately
  200 mOsm/kg in response to exogenous ADH.

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Water Restriction Tests

• Interpretation
• Normal subjects and primary polydipsia
• Urine osms are greater than plasma Osms after
  water restriction.
• Urine osms increase minimally (lt10) after
  exogenous ADH.
• Central Diabetes Insipidus
• Urine osms remain less than plasma osms after
  water restriction.
• After ADH is given, urine osms increase 100 in
  complete CDI and over 50 in partial CDI.
• Nephrogenic Diabetes Insipidus
• Urine osms remain less than plasma osms.
• After ADH, urine osms increase by less than 50.

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Water Restriction Test

• Plasma ADH levels are measured at baseline and
  after water restriction in order to differential
  CDI, NDI, and primary polydipsia, in case the
  water restriction test is equivocal.
• If there is an appropriate rise in ADH in
  response to the rising plasma osmolality, central
  DI is excluded.
• If there is an appropriate elevation in urine
  osmolality as the plasma ADH rises, nephrogenic
  DI is excluded.
• Plasma ADH levels can be misleading in primary
  polydipsia since chronic over-hydration induces
  partial suppression of ADH release, mimicking the
  pattern in central DI.

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Treatment

• Treatment is primarily aimed at decreasing the
  urine output, usually by increasing the activity
  of ADH.
• Replacement of previous and ongoing fluid losses
  is also important, either with oral water intake
  or IVF such as D5W if the patient is unable to
  take fluids by mouth.
• There are several medications available for the
  treatment of CDI, of which desmopressin is the
  most common.

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Desmopressin

• Desmopressin is a two-amino acid substitute of
  ADH that has potent antidiuretic activity but no
  vasopressor activity.
• It is also known as dDAVP, which stands for
  1-deamino-8-D-arginine vasopressin.
• It is currently the drug of choice for long-term
  therapy of CDI to control polyuria.
• It is safe during pregnancy for both the mother
  and the fetus.

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Desmopressin

• The initial aim of therapy is to reduce nocturia,
  in order to provide adequate sleep.
• Thus, the first dose is usually given in the late
  evening to control nocturia.
• After that is achieved, control of daily diuresis
  is the goal.
• The size of and necessity for a daytime dose is
  determined by the effectiveness of the evening
  dose and any recurrence of polyuria during the
  day.

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Desmopressin

• It comes in a liquid form that is usually
  administered intranasally.
• The intranasal preparation can be delievered with
  a rhinal catheter or a metered nasal spray
  bottle.
• A initial dose of 10 micrograms of the intranasal
  form is given at bedtime.
• This dose is titrated up in 5 microgram
  increments as needed depending on the response of
  the nocturia.
• The typical daily maintenance dose is 10 to 20
  micrograms once or twice daily.

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Desmopressin

• An oral tablet preparation is also available.
• Absorption of the oral form is decreased 40-50
  when taken with meals.
• The oral form has about 1/10 to 1/20 the potency
  of the nasal form because only about 5 is
  absorbed from the gut.
• It is recommended to start with the nasal form
  before attempting a trial of oral therapy in
  order to ensure that the patient understands what
  constitutes a good antidiuretic response.

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Risks of Desmopressin

• Potential risks of desmopressin include water
  retention and the development of hyponatremia.
• This may occur because once dDAVP is given, the
  patient has nonsuppressible ADH activity and may
  be unable to excrete ingested water normally.
• This can be avoided by giving the minimum daily
  dose required to control the polyuria.

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Other Drugs

• For the vast majority of patients with CDI, dDAVP
  is readily available, safe, and effective.
• Therefore, it is rarely necessary to add other
  drugs to the regimen.
• The other agents available are less effective and
  associated with more adverse effects than
  desmopressin.
• Chlorpropamide, carbamazepine, and clofibrate can
  be used in cases of partial CDI and can lower the
  urine output by as much as 50.

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Other Drugs

• Chlorpropamide
• An oral hypoglycemic agent.
• Acts by promoting the renal response to ADH or
  dDAVP.
• The usual dose is 125 to 250 mg, once or twice a
  day.
• Higher doses may produce a somewhat greater
  response but also increase the risk of
  hypoglycemia.

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Other Drugs

• Carbamazepine
• An anticonvulsant.
• Enhances ADH release and raises the sensitivity
  of the collecting duct to it.
• 100 to 300 mg twice daily is the typical dose.

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Other Drugs

• Clofibrate
• A lipid lowering agent.
• Stimulates residual ADH production in the
  hypothalamus, therefore increasing ADH release
  from the posterior pituitary.
• 500 mg every six hours is the usual dose.

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Other Drugs

• Thiazide diuretics
• Can be used paradoxically to treat CDI.
• Act independent of ADH.
• Its effects are additive to those of other
  modalities.
• Work via a hypovolemia-induced increase in sodium
  and water reabsorption in the proximal tubule,
  thus decreasing water delivery to the
  ADH-sensitive sites in the collecting tubules and
  reducing urine output.

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Other Drugs

• NSAIDs
• Also act independent of ADH.
• Can be used with other agents in CDI.
• Work by inhibiting renal prostaglandin synthesis
  and decreasing the glomerular filtration rate.
• Can decrease urine output by up to 50.
• Not all NSAIDs are equally effective in all
  patients.

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References

• Bichet, Daniel G. Diagnosis of polyuria and
  diabetes insipidus. UpToDate. 2007.
• Makaryus, Amgad N. McFarlane, Samy I. Diabetes
  insipidus Diagnosis and treatment of a complex
  disease. Cleveland Clinic Journal of Medicine.
  Volume 73, Number 1, January 2006.
• Rose, Burton D Bichet, Daniel G. Treatment of
  central diabetes insipidus. UpToDate. 2007.
• Sands, Jeff M., Bichet, Daniel G. Nephrogenic
  Diabetes Insipidus. Ann Intern Med. 2006
  144186-194.