Diabetes insipidus is a condition characterized by excessive thirst and excretion of large
amounts of severely diluted urine, with reduction of fluid intake having no effect on the concentration
of the urine.
There are different types of DI, each with a different set of causes.
The most common type in humans is the neurological form, called Central DI, which involves a
deficiency of arginine vasopressin, also known as antidiuretic hormone.
The second common type of DI is nephrogenic diabetes insipidus, which is due to kidney
or nephron dysfunction caused by an insensitivity of the kidneys or nephrons to ADH.
DI can also be gestational, or present as an iatrogenic artifact of alcohol or some
types of drug abuse.
DI should not be confused with nocturia.
Although they have a common name, diabetes mellitus and diabetes insipidus are two entirely
separate conditions with unrelated mechanisms.
Both cause large amounts of urine to be produced, and the term "diabetes" is derived from the
Greek word meaning siphon.
However, diabetes insipidus is either a problem with the production of antidiuretic hormone
or kidney's response to antidiuretic hormone, whereas diabetes mellitus causes polyuria
via a process called osmotic diuresis, due to the high blood sugar leaking into the urine
and taking excess water along with it.
The incidence of diabetes insipidus in the general population is 3 in 100,000.
Signs and symptoms Excessive urination and also extreme thirst
are typical for DI.
The symptoms of excessive urination and extreme thirst are similar to what is seen in untreated
diabetes mellitus, with the distinction that the urine does not contain glucose.
Blurred vision is a rarity.
Signs of dehydration may also appear in some individuals, since the body cannot conserve
much of the water it takes in.
The extreme urination continues throughout the day and the night.
In children, DI can interfere with appetite, eating, weight gain, and growth, as well.
They may present with fever, vomiting, or diarrhea.
Adults with untreated DI may remain healthy for decades as long as enough water is consumed
to offset the urinary losses.
However, there is a continuous risk of dehydration and loss of potassium.
Diagnosis To distinguish DI from other causes of excess
urination, blood glucose levels, bicarbonate levels, and calcium levels need to be tested.
Measurement of blood electrolytes can reveal a high sodium level.
Urinalysis demonstrates a dilute urine with a low specific gravity.
Urine osmolarity and electrolyte levels are typically low.
A fluid deprivation test is another way of distinguishing DI from other causes of excessive
urination.
It is also used to help determine what DI is caused by:
a defect in ADH production a defect in the kidneys' response to ADH
This test measures changes in body weight, urine output, and urine composition when fluids
are withheld to induce dehydration.
The body's normal response to dehydration is to conserve water by concentrating the
urine.
Those with DI continue to urinate large amounts of dilute urine in spite of water deprivation.
In primary polydipsia, the urine osmolality should increase and stabilize at above 280
Osm/kg with fluid restriction, while a stabilization at a lower level indicates diabetes insipidus.
Stabilization in this test means, more specifically, when the increase in urine osmolality is less
than 30 Osm/kg per hour for at least 3 hours.
Sometimes measuring blood levels of ADH toward the end of this test is also necessary, but
is more time consuming to perform.
To distinguish between the main forms, desmopressin stimulation is also used; desmopressin can
be taken by injection, a nasal spray, or a tablet.
While taking desmopressin, a patient should drink fluids or water only when thirsty and
not at other times, as this can lead to sudden fluid accumulation in the central nervous
system.
If desmopressin reduces urine output and increases urine osmolarity, the hypothalamic production
of ADH is deficient, and the kidney responds normally to exogenous desmopressin.
If the DI is due to renal pathology, desmopressin does not change either urine output or osmolarity.
Whilst Diabetes Insipidus usually occurs with polydipsia, it can also rarely occur not only
in the absence of polydipsia but in the presence of its opposite, Adipsia.
"Adipsic diabetes insipidus" is recognised.
which is characterised by a marked absence of thirst even in response to hyperosmolality.
In some cases of Adipsic DI, the patient may also fail to respond to desmopressin.
If central DI is suspected, testing of other hormones of the pituitary, as well as magnetic
resonance imaging, particularly a Pituitary MRI, is necessary to discover if a disease
process is affecting pituitary function.
Most people with this form have either experienced past head trauma or have stopped ADH production
for an unknown reason.
Habit drinking is the most common imitator of diabetes insipidus at all ages.
While many adult cases in the medical literature are associated with mental disorders, most
patients with habit polydipsia have no other detectable disease.
The distinction is made during the water deprivation test, as some degree of urinary concentration
above isoosmolar is usually obtained before the patient becomes dehydrated.
Pathophysiology Electrolyte and volume homeostasis is a complex
mechanism that balances the body's requirements for blood pressure and the main electrolytes
sodium and potassium.
In general, electrolyte regulation precedes volume regulation.
When the volume is severely depleted, however, the body will retain water at the expense
of deranging electrolyte levels.
The regulation of urine production occurs in the hypothalamus, which produces ADH in
the supraoptic and paraventricular nuclei.
After synthesis, the hormone is transported in neurosecretory granules down the axon of
the hypothalamic neuron to the posterior lobe of the pituitary gland, where it is stored
for later release.
In addition, the hypothalamus regulates the sensation of thirst in the ventromedial nucleus
by sensing increases in serum osmolarity and relaying this information to the cortex.
Neurogenic/central DI results from a lack of ADH; occasionally it can present with decreased
thirst as regulation of thirst and ADH production occur in close proximity in the hypothalamus.
It is encountered as a result of hypoxic encephalopathy, neurosurgery, autoimmunity or cancer, or sometimes
without an underlying cause.
The main effector organ for fluid homeostasis is the kidney.
ADH acts by increasing water permeability in the collecting ducts and distal convoluted
tubules; specifically, it acts on proteins called aquaporins and more specifically aquaporin
2 in the following cascade.
When released, ADH binds to V2 G-protein coupled receptors within the distal convoluted tubules,
increasing cyclic AMP, which couples with protein kinase A, stimulating translocation
of the aquaporin 2 channel stored in the cytoplasm of the distal convoluted tubules and collecting
ducts into the apical membrane.
These transcribed channels allow water into the collecting duct cells.
The increase in permeability allows for reabsorption of water into the bloodstream, thus concentrating
the urine.
Nephrogenic results from lack of Aquaporin channels in the distal collecting duct.
It is seen in Lithium toxicity, hypercalcemia, hypokalemia or release of ureteral obstruction.
Hereditary forms of diabetes insipidus account for less than 10% of the cases of diabetes
insipidus seen in clinical practice.
Classification The several forms of DI are:
Neurogenic
Neurogenic diabetes insipidus, more commonly known as central diabetes insipidus, is due
to a lack of vasopressin production in the hypothalamus due to a range of causes.
The underlying causes of Central DI can include vascular, autoimmune, infection, sarcoidosis,
some drugs, surgery, head trauma, benign or metastatic pituitary-hypothalmic tumor, although
50% of cases are found to be idiopathic Nephrogenic
Nephrogenic diabetes insipidus is due to the inability of the kidney to respond normally
to vasopressin.
Dipsogenic Dipsogenic DI is due to a defect or damage
to the thirst mechanism, which is located in the hypothalamus.
This defect results in the inability for water deficit to trigger vasopressin secretion and
thirst.
Consequently, patients tend to develop hypernatremia and dehydration without seeking water to drink.
Gestational Gestational DI occurs only during pregnancy
and the postpartum period.
During pregnancy, women produce vasopressinase in the placenta, which breaks down ADH.
Gestational DI is thought to occur with excessive production and/or impaired clearance of vasopressinase.
Most cases of gestational DI can be treated with desmopressin, but not vasopressin.
In rare cases, however, an abnormality in the thirst mechanism causes gestational DI,
and desmopressin should not be used.
Diabetes insipidus is also associated with some serious diseases of pregnancy, including
pre-eclampsia, HELLP syndrome and acute fatty liver of pregnancy.
These cause DI by impairing hepatic clearance of circulating vasopressinase.
It is important to consider these diseases if a woman presents with diabetes insipidus
in pregnancy, because their treatments require delivery of the baby before the disease will
improve.
Failure to treat these diseases promptly can lead to maternal or perinatal mortality.
Treatment Central DI
Central DI and gestational DI respond to desmopressin which is given as intranasal or oral tablets.
Carbamazepine, an anticonvulsive medication, has also had some success in this type of
DI.
Also, gestational DI tends to abate on its own four to six weeks following labor, though
some women may develop it again in subsequent pregnancies.
In dipsogenic DI, desmopressin is not usually an option.
Nephrogenic DI Desmopressin will be ineffective in nephrogenic
DI and is treated by reversing the underlying cause and replacing the free water deficit.
The diuretic hydrochlorothiazide or indomethacin can be used to create mild hypovolemia which
encourages salt and water uptake in proximal tubule and thus improve nephrogenic diabetes
insipidus.
Amiloride has additional benefit of blocking Li uptake.
Thiazide diuretics are sometimes combined with amiloride to prevent hypokalemia.
It seems paradoxical to treat an extreme diuresis with a diuretic, and the exact mechanism of
action is unknown but the thiazide diuretics will decrease distal convoluted tubule reabsorption
of sodium and water, thereby causing diuresis.
This decreases plasma volume, thus lowering GFR and enhancing the absorption of sodium
and water in the proximal nephron.
Less fluid reaches the distal nephron, so overall fluid conservation is obtained.
Lithium-induced nephrogenic DI may be effectively managed with the administration of amiloride,
a potassium-sparing diuretic often used in conjunction with thiazide or loop diuretics.
Clinicians have been aware of lithium toxicity for many years, and traditionally have administered
thiazide diuretics for lithium-induced polyuria and nephrogenic diabetes insipidus.
However, amiloride has recently been shown to be a successful treatment for this condition.
Etymology The word "diabetes" comes from Latin diabētēs,
which in turn comes from Ancient Greek διαβήτης which literally means “a passer through;
a siphon”.
Ancient Greek physician Aretaeus of Cappadocia used that word, with the intended meaning
“excessive discharge of urine”, as the name for the disease.
Ultimately, the word comes from Greek διαβαίνειν, meaning “to pass through”, which is composed
of δια-, meaning “through” and βαίνειν, meaning “to go”.
The word “diabetes” is first recorded in English, in the form "diabete", in a medical
text written around 1425.
"Insipidus" comes from the French word insipide; from Latin language insipidus, from Latin:
in- "not" + sapidus "tasty" from sapere "have a taste" - meaning “lacking flavor or zest;
not tasty”.
This is because diabetes insipidus has no glycosuria.
References
External links The Diabetes Insipidus Foundation, Inc
Information on Diabetes Insipidus