CDI is caused by partial or complete deficiency of the antidiuretic hormone, arginine vasopressin. This deficiency usually results from damage to the hypothalamus or pituitary gland. In extremely rare cases, vasopressin deficiency is caused by a genetic mutation that is inherited as an autosomal dominant or autosomal recessive trait. In approximately one third of cases, no specific cause can be identified (idiopathic) and may be autoimmune in etiology. The hypothalamus is a portion of the brain that acts as a link between the brain and the endocrine systems. The hypothalamus releases neuro-hormones that influence the secretion of other hormones such as those that aid in the regulation of various metabolic process, growth, reproductive function and autonomic functions of the body. One of the substances secreted by the hypothalamus is vasopressin, which travels via nerve fibers to the posterior pituitary gland. The pituitary is a small gland located near the base of the brain that stores several hormones and releases them into the bloodstream as needed by the body. These hormones regulate many bodily functions. The posterior lobe of the pituitary gland is known as the neurophysis (neurohypophsyeal region), which stores hormones and eventually secretes them into the bloodstream. After the hypothalamus produces vasopressin, the hormone travels to the pituitary gland, and is stored in the neurophysis. Vasopressin is eventually released into the bloodstream as needed by the body. Vasopressin travels to the kidneys where it binds to receptor proteins found on the surface of certain kidney cells, initiating a process through which the kidneys reabsorb water into the body. Without proper levels of vasopressin, water is not reabsorbed and is lost through urination. Damage to the hypothalamus, pituitary gland or the connection between the hypothalamus and pituitary gland (pituitary stalk) may impair the production, transport, storage, or release of vasopressin, which in turn impairs the ability of the body to conserve water. Such damage may occur from trauma due to an accident or surgery (e.g., surgery to remove a tumor in the area), various infections, tumors such as a craniopharyngioma or a germinoma, a rare disease known as Langerhans cell histiocytosis, or a variety of inflammatory, vascular, or granulomatous diseases. In rare cases, CDI may be inherited as an autosomal dominant trait. Genetic diseases are determined by the combination of genes for a particular trait that are on the chromosomes received from the father and the mother. Dominant genetic disorders occur when only a single copy of an abnormal gene is necessary for the appearance of the disease. The abnormal gene can be inherited from either parent, or can be the result of a new mutation (gene change) in the affected individual. The risk of passing the abnormal gene from affected parent to offspring is 50% for each pregnancy regardless of the sex of the resulting child. Even rarer is an autosomal recessive mode of inheritance in which neither parent is affected but each carries an abnormal gene which when combined together in the offspring result in disease. Investigators have determined that some cases of inherited CDI are caused by disruptions or changes (mutations) of the arginine vasopressin (AVP) gene. Mutations of the AVP gene impair the production (synthesis) or secretion of vasopressin. The AVP gene is located on the short arm (p) of chromosome 20 (20p13). Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated “p” and a long arm designated “q”. Chromosomes are further sub-divided into many bands that are numbered. For example, “chromosome 11p13” refers to band 13 on the short arm of chromosome 11. The numbered bands specify the location of the thousands of genes that are present on each chromosome. Researchers believe that some cases of idiopathic CDI may be caused by autoimmune factors. Autoimmune disorders are caused when the body’s natural defenses against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons. In CDI, the body produces antibodies or lymphocytes that attack cells that secrete vasopressin. CDI may also occur as part of a larger syndrome or disorder including Wolfram syndrome or septo-optic dysplasia. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
DI is usually an acquired disorder, with central DI having different causes than does nephrogenic DI. In rare cases, central or nephrogenic DI may be an inherited disorder. Central DI has many possible causes. According to the literature, the principal causes of central DI and their oft-cited approximate frequencies are as follows:
Idiopathic DI Idiopathic central DI presumably develops when cells in the hypothalamus are damaged or destroyed. Identification of antibodies against AVP-secreting cells and advances in imaging techniques have made idiopathic cases less common than they previously were. Increasingly, the role of inflammation and autoimmunity in DI is being recognized. Cases of lymphocytic hypophysitis were possibly classified as idiopathic prior to improved imaging studies. This disorder is characterized by lymphocytic infiltration of the stalk and posterior pituitary. Magnetic resonance imaging (MRI) may show abnormalities in these structures. Antibodies directed against vasopressin cells have been found in patients with idiopathic central DI; however, these antibodies have also been found in patients with Langerhans cell histiocytosis (LCH) or germinomas, which indicates that this finding can not be considered a reliable marker of autoimmune etiology in central DI. Indeed, reliance on AVP antibodies may delay the diagnosis of LCH or germinoma. Given the possible diagnostic confusion, close clinical and MRI follow-up is necessary. Serial contrast-enhanced brain MRIs (every 3-6 months for the first 2 years) in patients with central DI who have pituitary stalk thickening may shorten the time to diagnosis of germinoma by as much as 1 year. The role of human chorionic gonadotropin (hCG) in the early diagnosis of germinoma is not fully established. A negative result for hCG in the cerebrospinal fluid (CSF) does not exclude germinoma. Tumor-associated DI Primary intracranial tumors causing DI include craniopharyngiomas, germinomas, and pineal tumors, among others. The appearance of other hypothalamic manifestations may be delayed for as long as 10 years in these cases. Craniopharyngioma is a benign tumor that arises from squamous cell nests in the primitive Rathke pouch. It is the most frequent pediatric intracranial neoplasm, accounting for nearly 54% of cases. Central DI insipidus and multiple pituitary hormone deficiencies are common manifestations in childhood craniopharyngiomas. Surgery is the preferred treatment. A retrospective study by Andereggen et al found that in patients who underwent craniopharyngioma surgery, the presence of postoperative diabetes insipidus was an independent risk factor for hypothalamic obesity (odds ratio 15.2). [8] Postoperative DI The frequency with which DI develops after neurosurgery varies with the surgery’s scope. Approximately 10-20% of patients experience DI after transsphenoidal removal of an adenoma, compared with 60-80% of those who have undergone excision of large tumors. A retrospective study by Tanji et al indicated that in patients who undergo endoscopic transsphenoidal surgery for pituitary adenoma, the Esposito grade for intraoperative cerebrospinal fluid leak predicts the likelihood of postoperative DI development. A higher Esposito grade was associated with a greater risk of DI. [9] A retrospective study by Saldarriaga et al of pediatric patients who underwent transsphenoidal surgery for adrenocorticotropic hormone– or growth hormone–secreting pituitary adenomas found that postoperatively, 26% of the patients developed diabetes insipidus, and 14% developed syndrome of inappropriate antidiuretic hormone secretion (SIADH). Combined risk factors for these postsurgical conditions included female sex, manipulation of the posterior pituitary and/or tumor invasion into the posterior pituitary, and cerebrospinal fluid leak or lumbar drain. [10] Not all cases of postoperative DI are permanent. In a German study of metabolic disturbances after transsphenoidal pituitary adenoma surgery, only 8.7% of DI cases persisted for more than 3 months. [11] Postoperative polyuria does not necessarily indicate DI. The most common causes of postoperative polyuria are excretion of excess fluid administered during surgery and an osmotic diuresis resulting from treatment for cerebral edema. [12] DI in head trauma Central DI can be an acute or chronic complication of head injury or subarachnoid hemorrhage. [7, 13] Risk factors for acute DI include penetrating trauma and severe head trauma. [7] Other forms of pituitary dysfunction (eg, adrenocorticotropic hormone deficiency) may accompany posttraumatic DI. [13] The dysfunction may be transient or, less commonly, may develop gradually. [14] Hereditary central DI Approximately 10% of central DI cases are familial (although some experts suggest that familial DI may be underdiagnosed). [15] Most of these cases show autosomal dominant inheritance and result from a defect in the AVP-NP2 gene on chromosome 20p13. The defect results in the production of mutant prohormone that is toxic to the neuron and eventually destroys it. [16, 17, 18] There are also autosomal recessive forms of DI, which result from defects in the AVP-NP2 (AVP neurophysin) gene, as well as in the WFS1 gene. The latter gene encodes for wolframin, a tetrameric protein that may serve as a novel endoplasmic reticular calcium channel in pancreatic beta cells and neurons. Mutations in WFS1 lead to Wolfram syndrome, which is also known by the acronym DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness). [19] Another recessive form of central DI results from the production of biologically inactive AVP. In addition, an X-linked form of neurohypophyseal DI exists. A specific genetic defect has not been identified. [3] Genetic testing to determine the specific etiology can obviate the search for another cause. [3] Finding a genetic anomaly will also answer recurrence risk questions for the family, and may prove to be helpful with treatment options. Additional causes Other causes of central DI include the following:
A study by Lee et al found that 12% of cardiac arrest survivors treated with targeted temperature management (TTM) developed central DI, with these patients demonstrating poor neurologic outcomes and high mortality rates. The study involved 385 patients, 45 of whom were confirmed to have central DI. Multivariate analysis indicated that in cardiac arrest survivors treated with TTM, independent risk factors for central DI include younger age, nonshockable rhythm, long downtime, and asphyxial cardiac arrest. [20] In adults, nephrogenic DI most often develops as a result of lithium toxicity or hypercalcemia. Impairment of urinary concentration occurs in up to 20% of patients taking lithium, as a result of dysregulation of the aquaporin system in principal cells of the collecting duct. [21, 22] Prolonged elevation of serum calcium concentrations above 11 mg/dL (2.75 mmol/dL can also impair urinary concentrating ability. Other causes of acquired nephrogenic DI include the following:
In addition to lithium, other drugs that can reduce urinary concentrating ability include the following: Hereditary nephrogenic DI Hereditary nephrogenic DI is relatively rare. [4] The most common inherited form results from mutations in the AVP receptor 2 gene (AVPR2) on chromosome Xq28. [23] Defects in the AVP receptor cause resistance to the antidiuretic effect of vasopressin. Because hereditary nephrogenic DI is an X-linked disorder, most cases occur in males; however, cases occasionally arise in females as a result of skewed X inactivation. [24] Approximately 1% of familial nephrogenic DI cases result from mutations in AQP2 (aquaporin 2), a gene on chromosome 12q13 that gives rise to a water channel that is expressed exclusively in the kidney’s collecting ducts. Autosomal recessive and autosomal dominant forms of nephrogenic DI from AQP2 mutations have been reported. [3] |
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