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Definition of Diabetes Insipidus
Diabetes insipidus (DI) is an uncommon medical condition caused by the decreased secretion or action of the antidiuretic hormone (ADH), commonly known as vasopressin. This condition is characterized by polyuria (urinary output > 3 L/day) and hypo-osmolar urine (osmolality < 300 mOsm/kg).
Central DI and nephrogenic DI are the two common types of DI.
Central DI manifests with a decreased secretion of ADH, while nephrogenic DI is characterized by the inability of the kidneys to concentrate urine despite the availability of ADH. This is known as ADH resistance.
Anatomy of the Pituitary Gland
The pituitary gland (hypophysis) lies in a pocket (hypophyseal/sphenoidal fossa) of the sphenoid bone at the base of the brain. It is divided into anterior (adenohypophysis) and posterior (neurohypophysis) lobes.
The neurohypophysis is controlled by the nervous system and produces the hormones vasopressin and oxytocin. ADH, also known as vasopressin, regulates blood pressure and the amount of water excreted by the kidneys. Oxytocin, on the other hand, plays an important role in parturition and breastfeeding.
Antidiuretic Hormone (ADH)
ADH is synthesized in the suprachiasmatic nucleus of the hypothalamus and ultimately transported to the posterior pituitary via the pituitary stalk. ADH release normally occurs following stimulation of the osmoreceptors, usually due to increased plasma osmolality.
ADH acts on the V2 receptors in the distal kidney tubules and collecting ducts by causing the insertion of aquaporin channels, which increase the water permeability of the collecting ducts. This in turn allows reabsorption; 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 a net water loss leading to the increased osmolality of body fluids.
ADH also promotes the release of von Willebrand factor and factor VIII from the endothelium. This is pharmacologically important as vasopressin analogs are used in the management of von Willebrand Disease (vWD) type I and Hemophilia A.
At supra-physiological levels, ADH acts on V1 receptors to cause vasoconstriction, and hence the term vasopressin.
Epidemiology and Etiology of DI
DI is uncommon in the United States and has a prevalence of 3 cases per 100,000 individuals. Additionally, DI is neither gender-related nor linked to a certain race or ethnic group. It is often an acquired disorder; however, 1-2% of cases are believed to be hereditary.
The central and nephrogenic forms of DI have different etiologies and are discussed separately.
Etiology of central DI
ADH 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 DI. The etiology of one-third of cases is attributed to an unknown cause.
It is important to note that the term “idiopathic central DI” is not accurate. High-resolution MRI has indicated the majority of these cases to be linked to an abnormality in the hypothalamus. Additionally, several patients previously diagnosed with “idiopathic central DI” have been found to have antibodies against ADH-secreting cells, thus suggesting the role of autoimmunity.
Craniopharyngiomas and pineal tumors are the most common CNS tumors associated with DI. Pituitary surgeries, especially open traditional approaches, are associated with central DI in about 80% of cases. Central DI occurring after surgeries is usually temporary and resolves in about three months in 90% of cases.
Severe head trauma, especially if accompanied by subarachnoid hemorrhage, has been associated with an increased risk of central DI, which could develop into a chronic condition.
The most common cause of central DI is idiopathic CDI (autoimmune antibody-mediated destruction of vasopressin-secreting hypothalamic cells).
Central DI after trauma to or around the region of the pituitary and hypothalamus, or following neurosurgery is common. Lesions may exhibit either a transient, permanent, or triphasic pattern, with the latter being observed frequently in clinical practice.
Other factors responsible for central DI include the following:
- Vascular causes including hemorrhage
- Infective causes such as meningoencephalitis
- Tumors, both primary (pituitary tumors) and secondary (tumor infiltration including craniopharyngiomas, nearby vascular tumors, or metastases from the lungs)
- Idiopathic causes such as autoimmune hypophysitis
- Hypoxic encephalopathy
Hereditary causes: Although rare, DI may be inherited via autosomal dominant and recessive patterns, resulting in defects in the ADH gene and problems in ADH synthesis. Wolfram syndrome is an inherited condition that results in ADH dysregulation. It is a rare autosomal recessive disorder in which patients present with diabetes insipidus, diabetes mellitus, optic atrophy, and deafness (DIDMOAD).
Infiltration observed in histiocytosis and sarcoidosis may also result in central DI.
Etiology of nephrogenic DI
Nephrogenic DI is commonly encountered in patients with lithium toxicity, hypokalemia, and hypercalcemia, although patients with chronic kidney disease could also develop this condition. Lithium interferes with the function of the collecting ducts of the nephrons, which manifests as an inability to concentrate urine. Sickle cell disease and amyloidosis are also linked to nephrogenic DI.
Drugs linked to nephrogenic DI include amphotericin B, ofloxacin, and orlistat. Pregnancy may transiently cause gestational DI, which usually resolves after delivery.
Etiology of hereditary DI
Hereditary forms of DI are rare and account for approximately 10% and 1% of nephrogenic and central DI cases, respectively. Mutations in the arginine-vasopressin NP2 gene (AVP-NP2) on chromosome 20p13 are associated with a mutated, toxic form of ADH that eventually leads to the destruction of ADH-secreting cells and causes ADH deficiency. AVP-receptor-2-gene mutations on chromosome Xq28 result in nephrogenic DI due to ADH resistance.
Pathophysiology of DI
Regulation of water balance is dependent on three factors, namely, thirst, ADH, and kidney performance. A failure in any of these factors could eventually result in DI.
Physiologically, ADH increases water reabsorption in the collecting ducts of the nephrons and regulates the amount of water excreted by the kidneys. When an individual is dehydrated, ADH secretion increases and results in the reabsorption of free water. In the absence of ADH (central DI), and cases when the kidneys are resistant to ADH (nephrogenic DI), water cannot be reabsorbed; instead, it is increasingly excreted by the kidneys and results in a high volume of dilute urine.
Central DI could be related to defects in the following:
- Hypothalamic osmoreceptors responsible for measuring and controlling blood osmolality
- Supraoptic and paraventricular hypothalamic nuclei responsible for ADH synthesis and secretion
- Supraopticohypophyseal tract responsible for the transport of ADH to the pituitary gland for secretion
In nephrogenic DI, kidneys lose their ability to concentrate urine due to ADH resistance.
Clinical Presentation of DI
Patients with DI present with polyuria, polydipsia, and nocturia. Nocturia, or increased urination at night, is an important manifestation of true DI in contrast to psychogenic DI. Urinary output is > 3 L per day and may increase up to 20 L per day.
It is important to consider surgical and trauma history to exclude possible neurosurgery-related central DI or post-traumatic brain injury-related DI.
Infants with hereditary DI present with crying, polyuria, and hyperthermia due to dehydration. At later stages, they show growth retardation and weight loss. If the anterior pituitary in patients is affected, other hormonal deficiencies may also be evident.
A physical examination is not very helpful in these patients unless there is limited access to water; this is when clinical signs of dehydration can be assessed. The urinary bladder is enlarged in patients with DI.
Symptoms of hypernatremia such as lethargy, thirst, weakness, irritability, confusion, and convulsions may be present and coma may occur.
Progression and Complications of DI
Although rare, there exists a possibility of DI-related death. The reasons for fatalities include dehydration, an increase in serum sodium levels, and cardiovascular collapse.
Severe dehydration may occur in some cases due to excessive water loss. Dehydration manifests as confusion and irritability, dizziness, headache, and dryness of the mouth.
Fluid accumulation may occur after standard treatment for DI with desmopressin and can lead to hyponatremia (with symptoms including headache, vomiting, and seizures). Hyponatremia can be prevented by monitoring sodium levels after commencing desmopressin therapy.
If thirst is not adequately sated or if there is no access to water, hypernatremia and associated clinical manifestations may develop.
Diagnostic Workup of DI
The first and most important step in the diagnostic workup of a patient suspected to have DI is to confirm a urinary output volume > 3 L/day. Therefore, a 24-hour urine collection is indicated.