Patients with diabetes insipidus present with polyuria, urinary output > 3 L per day and can be central or nephrogenic in origin. In central diabetes insipidus, there is a decrease in the secretion of antidiuretic hormone (ADH), while, in nephrogenic diabetes insipidus, the kidneys are unable to concentrate the urine due to ADH resistance.

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water bottles

Image: “Water bottles.” by Zeynel Cebeci – Own work. License: CC BY-SA 4.0


Definition of Diabetes Insipidus

Diabetes insipidus (DI) is an uncommon medical condition due to the decreased secretion or action of antidiuretic hormone (ADH), also called vasopressin. This condition is characterized by polyuria, urinary output more than 3 L per day, and hypo-osmolar urine, the urinary osmolality < 300 mOsm/kg.

There are two forms of diabetes insipidus i.e. central DI and nephrogenic DI.

In the central form of the disease, there is a decreased secretion of antidiuretic hormone (ADH). On the other hand, nephrogenic DI is characterized by the inability of the kidneys to concentrate urine despite the availability of ADH. In simple words, there is ADH resistance in nephrogenic DI.

Anatomy of Pituitary Gland

The pituitary gland, also known as the hypophysis lies in a pocket of the sphenoid bone, known as the hypophyseal/sphenoidal fossa, at the base of the brain. It is divided into the anterior (adenohypophysis) and the posterior pituitary glands (neurohypophysis).

The neurohypophysis is controlled by the nervous system and only produces two hormones: vasopressin and oxytocin. Antidiuretic hormone (ADH), also known as vasopressin, regulates body water levels and blood pressure. Oxytocin, on the other hand, plays important roles in parturition and breast feeding.

Antidiuretic Hormone (ADH)

ADH is synthesized in the suprachiasmatic nuclei of the hypothalamus and is ultimately transported to the posterior part of the pituitary via the stalk of the pituitary. ADH release normally occurs following stimulation of osmoreceptors usually due to increased plasma osmolality.

ADH acts on V2 receptors at the distal kidney tubule and the collecting duct by causing insertion of aquaporin channels thus increasing their permeability to water. The resulting increased permeability of the collecting ducts causes reabsorption of water to occur as water enters the hypertonic interstitium of the renal pyramids, thus concentrating the urine.

In the absence of ADH, the urine is hypotonic to plasma (dilute urine), urine volume is increased, and there is net water loss leading to increased osmolality of body fluids.

ADH also promotes release of von Willebrand factor and factor VIII from the endothelium. This is important pharmacologically as vasopressin analogues are used in the management of von Willebrand Disease (vWD) type I and Hemophilia A.

At supra-physiologic levels, ADH acts on V1 receptors to cause vasoconstriction, hence the term vasopressin.

Epidemiology and Etiology of Diabetes Insipidus

Diabetes insipidus is uncommon in the United States and has a prevalence of 3 per 100,000. Additionally, DI is neither gender-related nor linked to certain race or ethnicities. DI is often an acquired disorder but 1-2% of cases are believed to be hereditary.

Central DI and nephrogenic DI have different etiologies and are discussed separately.

Etiology of central diabetes insipidus

pineal tumor

Image: “Pineal Tumor” by BruceBlaus – Own Work. License: CC BY-SA 4.0

An antidiuretic hormone is produced by the hypothalamus and secreted by the posterior pituitary gland (neurohypophysis), therefore, central DI is often related to a pituitary defect that leads to a decrease in ADH secretion.

Brain and pituitary tumors, cranial surgery and head trauma are the three most common causes of central diabetes insipidus. The etiology of one-third of the cases is attributed to an unknown cause.

It is important to note that the term “idiopathic central DI” is not preferred because the majority of these cases have been found to have an abnormality in the hypothalamus with the more recent and advanced high-resolution MRI. Additionally, a larger number of the patients previously diagnosed with idiopathic central DI have been found to have antibodies against ADH-secreting cells emphasizing the role of autoimmunity.

Craniopharyngiomas and pineal tumors are the most common CNS tumors associated with DI.

Surgeries on the pituitary gland, especially open traditional approaches, are associated with central DI in about 80% of the cases. Surgical central DI is usually temporary and resolves in about 3 months in 90% of the cases.

Finally, severe head trauma, especially if accompanied by subarachnoid hemorrhage, has been shown to be associated with an increased risk of central DI which could become chronic.

  1. The most common cause of central diabetes insipidus is idiopathic CDI (autoimmune antibody mediated destruction of the vasopressin secreting hypothalamic cells).

  2. Central DI after trauma or neurosurgery to or around the region of the pituitary and hypothalamus is also common. This lesion may exhibit one of the following 3 patterns: transient, permanent, triphasic; with the latter being observed more often clinically.

  3. Other important causes of central diabetes insipidus include

    • Vascular causes such as hemorrhage
    • Infective causes such as meningoencephalitis
    • Tumors both primary (pituitary tumors) and secondary may result in central diabetes insipidus. Tumor infiltration such as by craniopharyngiomas, nearby vascular tumors, or metastases from other areas such as the lung is examples of secondary causes.
    • Idiopathic causes such as autoimmune hypophysitis
    • Hereditary causes: diabetes insipidus may rarely be inherited via inheritance patterns such as both autosomal dominant and recessive, resulting in defects in the ADH gene. This results in the problem in the synthesis of the ADH. An example of an inherited syndrome that results in a ADH dysregulation among other things is the Wolfram syndrome. Wolfram syndrome is a rare autosomal recessive disorder where the patient presents with: Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy and Deafness (DIDMOAD).
    • Infiltration as in histiocytosis or sarcoidosis may also result in central diabetes insipidus.
    • Hypoxic encephalopathy.

Etiology of nephrogenic diabetes insipidus

Nephrogenic DI is commonly encountered in patients with lithium toxicity, hypokalemia and hypercalcemia, while patients with chronic kidney disease could also develop DI. Lithium causes dysfunction of the collecting duct in the kidneys and this manifests as an inability to concentrate the urine. Sickle cell disease and amyloidosis are also linked to nephrogenic DI.

Other medications linked to nephrogenic DI include amphotericin B, ofloxacin and orlistat.

Pregnancy may also transiently cause gestational diabetes insipidus, which usually resolves after pregnancy.

Etiology of hereditary diabetes insipidus

Hereditary forms of DI are rare and account for approximately 10% of central DI cases and 1% of nephrogenic DI. Mutations in the arginine-vasopressin NP2 gene (AVP-NP2) on chromosome 20p13 are associated with a mutated and toxic form of ADH that eventually leads to the destruction of ADH secreting cells and ADH deficiency. AVP receptor 2 gene mutations on chromosome Xq28 result in nephrogenic DI due to ADH resistance.

Pathophysiology of Diabetes Insipidus

Water balance regulation is dependent on three main factors: thirst, ADH and the kidneys. A failure in any of these three factors would eventually result in DI.

Physiologically, ADH increases the water reabsorption in the collecting ducts of nephron and regulate the water content of the body. In dehydration, the secretion of ADH increases to reabsorb more free water. In the absence of ADH (central DI), and when kidneys are resistant to ADH (nephrogenic DI), the water cannot be reabsorbed and increasingly excreted by the kidneys producing high volume diluted urine.

The central DI could also be related to a defect in the hypothalamic osmoreceptors responsible for measuring and controlling blood osmolality, or it could be related to a defect in the supraoptic and paraventricular hypothalamic nuclei responsible for ADH synthesis and secretion. Finally, it could be related to a defect in the supraopticohypophyseal tract responsible for the transport of ADH to the pituitary for secretion.

In nephrogenic DI, the kidneys lose the ability to concentrate the urine due to ADH resistance.

Clinical Presentation of Diabetes Insipidus

Patients with DI present with polyuria, polydipsia and nocturia. Nocturia, increased urination at night time, is an important manifestation of true DI in contrast to psychogenic DI. Urinary output is more than 3 L per day and may reach up to 20 L per day.

It is important to enquire about surgical and trauma history to exclude possible neurosurgery-related central DI or post-traumatic brain injury DI.

Infants with hereditary DI present with crying, polyuria and hyperthermia due to dehydration. At later stages, these infants show growth retardation and weight loss.

If the patient’s etiology has also affected the anterior pituitary, other hormonal deficiencies can be evident at presentation.

A physical examination is not very helpful in these patients unless there is limited access to free water and then dehydration will be appreciated. An enlarged urinary bladder can be identified in patients with DI.

Symptoms of hypernatremia can also be present: lethargy, thirst, weakness, irritability, confusion, convulsions and even coma.

Progression and Complications of Diabetes Insipidus

Though rare, there is a probability of DI related death. The reason for the death is the associated dehydration, increase in the serum sodium concentration, and cardiovascular collapse.

Complications

  1. Dehydration

Due to excess water loss, there might occur severe dehydration in some of the cases. The dehydration will manifest as that of the confusion and irritability, dizziness, head ache and the mouth dryness.

  1. Hyponatremia

Due to the treatment with the diabetes insipidus such as desmopressin and other therapy, there can occur accumulation of the fluid leading to the hyponatremia (with symptoms like headache, vomiting, seizures). This is prevented by means of monitoring the sodium level after starting the therapy with the desmopressin.

  1. Hypernatremia

If the thirst is not adequate or if there occurs inability to have access to water, this leads to the development of hypernatremia and all its associated clinical manifestations.

Diagnostic Workup of Diabetes Insipidus

The first and most important step in the diagnostic workup of a patient suspected to have DI is to confirm the urinary output volume of more than 3 L per day. A 24-hour urine collection is indicated. A urine output of less than 2 L per day without hypernatremia excludes DI. Another important criterion for the diagnosis of DI is the confirmation of low urinary osmolality (< 300 mOsm/kg) or low urinary specific gravity (< 1.005) in the presence of raised plasma osmolality (>287 mOsm/kg).

A supervised water deprivation test may be performed to confirm DI. The urine specific gravity, urine osmolarity, plasma osmolarity, serum sodium and body weight are hourly measured. The urine specific gravity of < 1.005 and/or urinary osmolality of < 300 mOsm/Kg confirms the diagnosis of DI when body weight reduces by 5% or the patient has developed hypernatremia and/or increased serum osmolarity. If serum ADH levels are normal, the diagnosis of nephrogenic DI is made. If serum ADH levels are low, the diagnosis of central DI is made.

Patients with primary polydipsia have a low plasma osmolarity, along with increased urine volume and decreased urine osmolarity.

Normal pituitary gland on MRI (T1 sagittal without contrast enhancement). The arrow points at the posterior pituitary (intense signal), and the arrowhead at the anterior pituitary.

Image: “Normal pituitary gland with hyperintensity signal of the posterior pituitary on a T1-weighted MRI. In patients with central DI, there is a loss of this hyperintensity signal.” by Hellerhoff – Own Work. License: CC BY-SA 3.0

An “ADH challenge test” may be performed to differentiate between central and nephrogenic DI. A synthetic ADH (desmopressin) is given to the patient then urine volume and urine osmolarity are measured. In central DI, urine volume will be decreased and urine osmolarity will increase due to the increased reabsorption of free water; while in nephrogenic DI, there will be no change or slight change as there is persistent resistance to the ADH.

Other laboratory investigations are also helpful in patients with DI and include serum electrolytes and glucose. In patients with nephrogenic DI, serum calcium can be elevated (hypercalcemia) and serum potassium (hypokalemia) can be low.

Brain imaging with high-resolution MRI can reveal loss of hyperintensity of the posterior pituitary on T1-weighted images in central DI. Measurement of other pituitary hormones is indicated if the patient has symptoms attributed to panhypopituitarism.

Differential diagnosis

  1. Hypertrophy of the prostrate

  2. Polydipsia of psychogenic in origin

  3. Diuresis of osmotic in origin.

Management of Diabetes Insipidus

The majority of the patients with DI can drink enough water to replace fluid loss, however, if the patient is unable to drink water then intravenous fluid replacement therapy is indicated. Patients with dehydration due to DI present with hypernatremia, and slow correction of hypernatremia is needed. The aim should be to reduce serum sodium by 0.5 mEq/L per hour and this can be achieved by a fluid flow rate of 500 mL/h.

In central DI, desmopressin can be used to replace ADH. Desmopressin is available in intranasal, oral and parenteral formulations and should be administered 2-3 times per day. If desmopressin is not enough to correct central DI, indomethacin and carbamazepine can be used as adjunctive therapy.

Patients with nephrogenic DI might also benefit from indomethacin. Discontinuation of lithium or other offending drugs in nephrogenic DI can also be helpful. If the cause of nephrogenic DI is hypercalcemia or hypokalemia, these electrolyte imbalances should be appropriately treated.

Unfortunately, recent advances in neurosurgical techniques only marginally reduced the risk of postoperative DI. The best option to treat postoperative DI currently is to closely monitor patients who undergo pituitary surgery with recurrent fluid intake and urinary output measurements. The majority of these cases develop only temporary DI and are resolved spontaneously.

Prevention of Diabetes Insipidus

The disease cannot be prevented as such. But the complications which develop in the disease can be avoided by means of adopting the right therapeutic regimen including appropriate dose modification for the desmopressin. The prompt treatment of the head trauma and the space occupying lesion of the CNS also helps in preventing the development of this condition.

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