Deficiencies of Vasopressin

Secretion and Action

Diabetes Insipidus
Sagittal view of the head demonstrating the position of
the neurohypophysis
Idealized schematic of the normal
physiologic relationships among
Plasma Osmolality, Plasma
Vasopressin (AVP), Urine
Osmolality, and Urine Volume
Diabetes Insipidus is the excretion of a large volume of
hypotonic, insipid (tasteless) urine, usually manifested by polyuria
(increased urination) and polydipsia (increased thirst).

The large volume, usually in excess of 50 to 60 mL/kg/day,

must be distinguished from increased frequency of small
volumes and from large volumes of isotonic or hypertonic
urine, both of which have other clinical significance.
Clinical Characteristics
 Decreased secretion or action of AVP usually manifests as
diabetes insipidus, a syndrome characterized by the production of
abnormally large volumes of dilute urine.

 The 24-hour urine volume is >50 mL/kg body weight, and the
osmolarity is <300 mosmol/L.
The polyuria produces symptoms of urinary frequency, enuresis,
and/or nocturia, which may disturb sleep and cause mild daytime
fatigue or somnolence.

It also results in a slight rise in plasma osmolarity that stimulates

thirst and a commensurate increase in fluid intake (polydipsia).

Overt clinical signs of dehydration are uncommon unless fluid

intake is impaired.
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.

 It can be caused by a variety of congenital, acquired, or genetic

disorders, but in about 50% of all adult patients it is idiopathic
(Table 340-1).
The surgically induced forms of pituitary DI usually appear
within 24 hours and then go through a 2- to 3-week interim period
of inappropriate antidiuresis, after which they may or may not
recur.

The genetic form usually is transmitted in an autosomal dominant

mode and is caused by diverse mutations in the coding region of
the AVP–neurophysin II (or AVP-NPII) gene.
All the mutations alter one or more amino acids known to be
critical for correct folding of the prohormone, thus interfering with
its processing and trafficking through the endoplasmic reticulum.

The AVP deficiency and DI develop gradually several months to

years after birth, progressing from partial to severe and permanent
DI.

They appear to result from accumulation of misfolded mutant

precursor followed by selective degeneration of AVP-producing
magnocellular neurons.
An autosomal recessive form due to an inactivating mutation in
the AVP portion of the gene, an X-linked recessive form due to an
unidentified gene on Xq28, and an autosomal recessive form due
to mutations of the WFS 1 gene responsible for Wolfram's
Syndrome [Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy,
and Neural Deafness (DIDMOAD)] have also been described.
A primary deficiency of plasma AVP also can result from
increased metabolism by an N-terminal aminopeptidase produced
by the placenta.

It is referred to as Gestational DI since the signs and symptoms

manifest during pregnancy and usually remit several weeks
after delivery.
 Secondary Deficiencies of AVP result from inhibition of secretion
by excessive intake of fluids.

They are referred to as Primary Polydipsia and can be divided

into three subcategories.

1. 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.

2. The second subtype, Psychogenic Polydipsia, is not associated

with thirst, and the polydipsia seems to be a feature of psychosis
or obsessive compulsive disorder.

3. The third subtype, Iatrogenic Polydipsia, results from

recommendations to increase fluid intake for its presumed health
benefits.
Primary deficiencies in the antidiuretic action of AVP result in
Nephrogenic DI (Table 340-1).

They can be genetic, acquired, or drug induced.

The Genetic Form usually is transmitted in a semirecessive X-

linked manner and is caused by mutations in the coding region of
the V2 receptor gene that impair trafficking and/or ligand binding
of the mutant receptor.
Autosomal recessive or dominant forms are caused by AQP2 gene
mutations that result in complete or partial defects in trafficking
and function of the water channels in distal and collecting tubules
of the kidney.
Secondary deficiencies in the antidiuretic response to AVP result
from polyuria per se.

They are caused by washout of the medullary concentration

gradient and/or suppression of aquaporin function.

They usually resolve 24–48 hours after the polyuria is corrected

but can complicate interpretation of some acute tests used for
differential diagnosis.
Pathophysiology
 When the secretion or action of AVP falls below 80–85% of
normal, urine concentration ceases and the rate of urine output
rises to symptomatic levels.
If the defect is due to Pituitary, Gestational, or Nephrogenic DI,
the polyuria results in a small (1–2%) decrease in body water and
a commensurate increase in plasma osmolarity and sodium
concentration that stimulate thirst and a compensatory increase in
water intake.

As a result, hypernatremia and otherovert physical or laboratory

signs of dehydration do not develop unless the patient also has a
defect in thirst or fails to drink for some other reason.
The severity of the antidiuretic defect varies markedly from
patient to patient.

In some, the deficiencies in AVP secretion or action are so

severe that even an intense stimulus such as nausea or severe
dehydration does not raise plasma AVP enough to concentrate
the urine.
 In others, the deficiency is incomplete, and a modest stimulus
such as a few hours of fluid deprivation, smoking, or a
vasovagal reaction increases plasma AVP sufficiently to raise
urine osmolarity as high as 800 mosmol/L.

The maximum achieved is usually less than normal, but that is the
case largely because maximal concentrating capacity is
temporarily impaired by chronic polyuria.
In primary polydipsia, the pathogenesis of the polydipsia and
polyuria is the reverse of that in pituitary, nephrogenic, and
gestational DI.

Thus, the 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.

Therefore, hyponatremia or clinically appreciable

overhydration is uncommon unless the polydipsia is very
severe or the compensatory water diuresis is impaired by a
drug or disease that stimulates or mimics endogenous AVP.
In the dipsogenic form of primary polydipsia, fluid intake is
excessive because the osmotic threshold for thirst appears to be
reset to the left, often well below that for AVP release.

When deprived of fluids or subjected to another acute osmotic or

nonosmotic stimulus, these individuals invariably increase plasma
AVP normally,
But the resultant increase in urine concentration is usually
subnormal because the individuals' renal capacities to
concentrate the urine also are blunted temporarily by chronic
polyuria.
Thus, the maximum level of urine osmolarity achieved is usually
indistinguishable from that in patients with partial pituitary,
partial gestational, or partial nephrogenic DI.

Patients with psychogenic or iatrogenic polydipsia respond

similarly to fluid restriction but do not complain of thirst and
usually offer other explanations for their high fluid intake.
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.
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.
 It can be performed on an outpatient basis if the necessary staff
and facilities are available.

To minimize patient discomfort, avoid excessive dehydration, and

maximize the information obtained, the test should be started in
the morning and continued with hourly monitoring of body weight,
plasma osmolarity and/or sodium concentration, urine volume,
and urine osmolarity until either of two endpoints is reached.
If fluid deprivation does not result in urine concentration
(osmolarity >300 mosmol/L, specific gravity >1.010) before body
weight decreases by 5% or plasma osmolarity/sodium rise above
the upper limit of normal, the patient has severe pituitary or
severe nephrogenic DI.

These disorders usually can be distinguished by administering

Desmopressin (0.03 mcg/kg SC or IV) and repeating the
measurement of urine osmolarity 1–2 hours later.

An increase of >50% indicates severe Pituitary DI, whereas a

smaller or absent response is strongly suggestive of Nephrogenic
DI.
Conversely, if fluid deprivation results in concentration of the
urine, severe defects in AVP secretion and action are excluded and
the question becomes whether the patient has Partial Pituitary DI,
Partial Nephrogenic DI, or Primary Polydipsia.

The maximum levels of urine osmolarity achieved before and

after desmopressin injection are of no help in this regard
because the values in the three groups vary widely and overlap
owing to impairment of renal concentrating capacity caused by
polyuria per se.
Therefore, another approach is needed to differentiate among them.

The easiest and least expensive method is to measure plasma

AVP
Before and during the fluid deprivation test and
Analyze the results in relation to the concurrent plasma
and urine osmolarity (Fig. 340-3).

This approach invariably differentiates partial nephrogenic DI

from Partial Pituitary DI and Primary Polydipsia.
It also differentiates partial pituitary DI from primary polydipsia if
plasma osmolarity and/or sodium are clearly above the normal
range when the hormone is measured.

However, the requisite level of hypertonic dehydration may be

difficult to produce by fluid deprivation alone when urine
concentration occurs.
Therefore, it is usually necessary to continue the fluid deprivation
and infuse hypertonic (3%) saline at a rate of 0.1 mL/kg per min
until plasma osmolarity/sodium measured every 20 to 30 minutes
reach or slightly exceed the upper limit of normal.

At that point the plasma osmolarity/sodium, which is usually

reached in 30 to 90 minutes, the measurement of plasma AVP
should be repeated and the result related to plasma
osmolarity/sodium is as before.
Relationship of plasma AVP to urine osmolarity (left) and plasma osmolarity (right)
before and during Fluid Deprivation–hypertonic Saline Infusion Test in patients who
are normal or have primary polydipsia (blue zones), pituitary diabetes insipidus (green
zones), or nephrogenic diabetes insipidus (pink zones).
An alternative method of differential diagnosis is MRI of the
Pituitary and Hypothalamus.

In most healthy adults and children, the posterior pituitary

emits a hyperintense signal in T1-weighted midsagittal images.

This "bright spot" is almost always present in patients with

primary polydipsia
But is invariably absent or abnormally small in patients with
pituitary DI.
It is usually also small or absent in Nephrogenic DI presumably
because of high secretion and turnover of AVP.

Thus, a normal bright spot virtually excludes pituitary DI,

argues against nephrogenic DI, and strongly suggests primary
polydipsia.

Lack of the bright spot is less helpful, however, because it is

absent not only in pituitary and nephrogenic DI but also in some
healthy adults and patients with empty sella who do not have DI
or AVP deficiency.
The other way to distinguish among the three basic types of DI is
a closely monitored trial of Desmopressin Therapy.
Treatment: Diabetes Insipidus
 The signs and symptoms of Uncomplicated Pituitary DI can be
eliminated completely by treatment with Desmopressin (DDAVP),
a synthetic analogue of AVP.

 DDAVP acts selectively at V2 receptors to increase urine

concentration and decrease urine flow in a dose-dependent
manner (Fig. 340-4).
It is also more resistant to degradation than is AVP and has a
three- to fourfold longer duration of action.

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 mcg 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.
When given in doses sufficient to normalize urinary osmolarity
and flow completely, desmopressin produces a slight (1–3%)
increase in total body water and a commensurate decrease in
plasma osmolarity and sodium concentration that rapidly
eliminates thirst and polydipsia.

Consequently, water balance is maintained and hyponatremia

does not develop unless the osmoregulation of thirst is also
impaired or fluid intake is excessive for another reason such as
a misconception about the need to prevent dehydration.
Fortunately, thirst abnormalities are rare in pituitary DI, and
other motivations to drink excessively usually can be eliminated
by patient education.

Therefore, Desmopressin usually can be given safely in doses

sufficient to normalize urine output completely, thereby
avoiding the inconvenience and discomfort of intermittent
escape otherwise needed to prevent water intoxication.
Effect of desmopressin
therapy on water balance in
a patient with uncomplicated
pituitary diabetes insipidus.

Note that treatment rapidly

reduces thirst and fluid
intake as well as urine
output to normal, with
only a slight increase in
body water (weight) and a
decrease in plasma
osmolarity/sodium.

Fig. 340-4
Primary polydipsia cannot be treated safely with desmopressin
or any other antidiuretic drug because eliminating the polyuria
does not eliminate the urge to drink.

Therefore, it produces hyponatremia and/or other signs of

water intoxication, usually within 24 to 48 hours if urine output
is normalized completely.
Patient education may eliminate Iatrogenic Polydipsia, but it is
largely ineffective in psychogenic or dipsogenic DI.

In these patients, the only help currently available is to try to

prevent water intoxication by warning about the use of drugs
that can impair urinary free-water excretion directly or
indirectly.
The polyuria and polydipsia of Nephrogenic DI are not affected
by treatment with standard doses of desmopressin.

If resistance is partial, it may be overcome by tenfold higher

doses, but this treatment is too expensive and inconvenient to be
useful chronically.
However, treatment with conventional doses of a thiazide diuretic
and/or amiloride in conjunction with a low-sodium diet and a
prostaglandin synthesis inhibitor (e.g., Indomethacin) usually
reduces the polyuria and polydipsia by 30–70% and may
eliminate them completely in some patients.

Side effects such as hypokalemia and gastric irritation can be

minimized by the use of amiloride or potassium supplements
and by taking medications with meals.
Adipsic Hypernatremia
Clinical Characteristics
 A defect in the thirst mechanism results in adipsic hypernatremia,
a syndrome characterized by chronic or recurrent Hypertonic
Dehydration.

 The hypernatremia varies widely in severity and usually is

associated with signs of hypovolemia such as tachycardia,
postural hypotension, azotemia, hyperuricemia, and hypokalemia.
Muscle weakness, pain, rhabdomyolysis, hyperglycemia,
hyperlipidemia, and acute renal failure may also occur.

DI usually does not exist at presentation but may develop

during rehydration.
Etiology
 Deficient thirst is usually due to hypogenesis or destruction of the
osmoreceptors in the anterior hypothalamus.

 Because of their proximity, the osmoreceptors that regulate AVP

secretion also are usually impaired.
These defects can result from various congenital malformations
of midline brain structures or
May be acquired due to diseases such as
1. Occlusions of the anterior communicating artery,
2. Primary or metastatic tumors in the hypothalamus,
3. Head trauma, surgery,
4. Granulomatous diseases such as sarcoidosis and
histiocytosis,
5. AIDS, and
6. Cytomegalovirus encephalitis.
Pathophysiology
 A deficiency of thirst results in a failure to drink enough water to
replenish obligatory renal and extrarenal losses, causing
hypertonic dehydration.

 In most patients, the response of AVP to osmotic stimulation is

also deficient (Fig. 340-5).
If the deficiency is partial, it may not be clinically apparent at
first because the hypertonicity and hypovolemia are severe enough
to stimulate the release of AVP in the small amounts necessary to
concentrate the urine.

However, when the hypertonicity and hypovolemia are reduced,

plasma AVP falls and polyuria develop, often before the
dehydration is corrected fully.

Patients with a complete lack of osmoregulation do not develop

DI at any level of hydration because they cannot osmotically
suppress or stimulate AVP secretion.
Therefore, a hyponatremic syndrome indistinguisable from
inappropriate antidiuresis may develop if rehydration is excessive.

In most patients, the neurohypophysis and the AVP response to

hemodynamic or emetic stimuli are normal.

In a few, however, the neurohypophysis is also destroyed,

resulting in a combination of chronic pituitary DI and hypodipsia
that is particularly difficult to manage.
Differential Diagnosis
 Adipsic hypernatremia usually can be distinguished clinically
from other causes of inadequate fluid intake (e.g., coma,
paralysis, restraints, absence of fresh water) that can also result in
hypertonic dehydration.

 Previous episodes and/or denial of thirst and failure to drink

spontaneously when the patient is conscious, unrestrained, and
hypernatremic are virtually diagnostic of adipsia.
The hypernatremia caused by excessive oral or intravenous
intake of sodium can also be distinguished by the history and/or
physical examination and laboratory signs of volume expansion
rather than contraction.
Treatment: Adipsic Hypernatremia
 Adipsic hypernatremia should be treated by administering water
orally if the patient is alert and cooperative or by using hypotonic
fluids (0.45% saline or 5% dextrose and water) via IV if the
patient is not.

 The amount of free water in liters required to correct the deficit

(FW) can be estimated from body weight in kg (BW) and the
serum sodium concentration in mmol/L (SNa) by the formula

FW = 0.5BW x [(SNa – 140)/140].

If serum glucose (SGlu) is elevated, the measured SNa should be
corrected (SNa*) by the formula
SNa* = SNa + [(SGlu – 90)/36].

This amount plus an allowance for continuing insensible and

urinary losses should be given over a 24- to 48-hour period.
Close monitoring of serum sodium as well as fluid intake and
urinary output is essential because, depending on the extent of
osmoreceptor deficiency (Fig. 340-5),
1. some patients will develop AVP-deficient DI, requiring
desmopressin therapy to complete rehydration;
2. others will develop hyponatremia and a syndrome of
inappropriate antidiuresis (SIAD)-like picture if overhydrated.
If hyperglycemia and/or hypokalemia are present, insulin and/or
potassium supplements should be given with the expectation that
both can be discontinued soon after rehydration is complete.

Plasma urea/creatinine should be monitored closely for signs

of acute renal failure.
Once the patient has been rehydrated, an MRI of the brain and
tests of anterior pituitary function should be performed to look for
the cause and collateral defects in other hypothalamic functions.

A long-term management plan to prevent or minimize

recurrence of the fluid and electrolyte imbalance also should be
developed.
This should include a practical method that can be used to
regulate fluid intake in accordance with day-to-day variations in
water balance.

The most effective way to do this is

1. to prescribe desmopressin to control DI if it is present and
2. teach the patient how to adjust daily fluid intake in
accordance with day-to-day changes in body weight or
serum sodium as determined by home monitoring
analyzers.
Prescribing a constant fluid intake is ineffective and potentially
dangerous
because it does not take into account the large, uncontrolled
variations in insensible loss that inevitably result from changes
in ambient temperature and physical activity.