NORD gratefully acknowledges Thomas A. Wilson, MD, Professor of Pediatrics and Chief, Division of Pediatric Endocrinology, Department of Pediatrics, State University of New York, Stony Brook, for his assistance in creating this report.
In CDI, symptoms may develop over time or abruptly and may affect individuals of any age. CDI is characterized by excessive thirst (polydipsia) and excessive urination (polyuria), even at night (nocturia). The severity and progression of CDI varies from case to case. Some individuals may have a severe form of the disorder (complete CDI) with little or no vasopressin activity. Others may have a mild form of the disorder (partial CDI) with residual vasopressin activity.
Without appropriate AVP secretion, individuals with central diabetes insipidus are unable to concentrate the urine by reabsorbing water in the kidneys. This results in obligatory excessive urine output of dilute urine. Consequently, individuals must drink excessively to prevent dehydration. In response to thirst, affected individuals may drink several gallons of water a day. If affected individuals are deprived of water for an extended period of time, rapid dehydration will occur. Thirst cravings can be strong enough to awaken people from sleep.
In infants, additional symptoms may occur including irritability, lethargy, vomiting, constipation and fever. If left untreated, repeated episodes of dehydration can potentially result in seizures, brain damage, developmental delays, and physical and mental retardation. However, with proper diagnosis and prompt treatment intelligence and development is usually normal unless more global problems in development of the brain are associated. Affected children may develop bedwetting (enuresis), fatigue, weight loss, and growth retardation.
Individuals with CDI are at risk of developing dehydration and cardiovascular symptoms including irregular heartbeats, fever, dry skin and mucous membranes, confusion, seizures, change in consciousness, and potentially coma. Affected adults may develop orthostatic hypotension, a condition in which there is a dramatic decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope).
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.)
CDI affects males and females in equal numbers and can occur at any age. Onset is more common between the ages of 10 and 20 years. The inherited form of CDI is extremely rare with fewer than 100 cases reported in the medical literature. CDI is estimated to occur in 1 out of every 25,000 individuals.
A diagnosis of CDI may be suspected based upon the identification of characteristic findings, specifically excessive thirst and excessive urination. A thorough clinical evaluation, a detailed patient history, and a variety of specialized tests may be used to confirm a diagnosis. Physicians may take blood and urine samples to determine the concentration of salts, and sugar within those samples. The ratio of these substances to water within the blood or urine is known as osmolality. Individuals with CDI have a high osmolality in their blood and a low osmolality in their urine. The urine osmolality may be estimated by the specific gravity, which is low in untreated diabetes insipidus.
Additional tests may be necessary to confirm a diagnosis or rule out other causes of diabetes insipidus. Assay of vasopressin in the circulation is problematic since it is unstable and has a short half-life. Copeptin is cosecreted with vasopressin and is more stable. Therefore, it provides a surrogate marker of vasopressin secretion. Affected individuals may also receive a diagnostic injection of the hormone arginine vasopressin or an analogue of vasopressin such as DDAVP (see below) to determine the kidneys’ response. Individuals with a different form of diabetes insipidus (i.e., nephrogenic diabetes insipidus) do not respond to vasopressin supplementation because in NDI the kidneys are resistant to the effects of vasopressin. Conversely, individuals with CDI respond to supplemental vasopressin treatment.
In some individuals an additional test, known as a water deprivation test, may be required to confirm a diagnosis. During this test, affected individuals cannot ingest any fluids and can only eat dry foods for a specific period of time. Blood and urine samples will be taken to measure serum sodium concentration or osmolality and urine output, osmolality or specific gravity. This dehydration provides a stimulus for vasopressin secretion which can be estimated by measuring copeptin concentrations or by the concentration of the urine. Serum vasopressin levels may be measured as well if handled appropriately. Body weight and vital signs are monitored to prevent excessive dehydration. This test may be used to distinguish between the various causes of diabetes insipidus.
Some individuals will have x-ray scans including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of CDI. A common finding on MRI in children with central diabetes insipidus is absence of the “bright spot” in the posterior sella which is normally thought to represent vasopressin containing neurons.
Ensuring proper fluid intake and reducing urine output are essential. Specific treatments include the administration of certain drugs. Specific therapy varies depending upon the severity of vasopressin deficiency. Individuals with the severe form of the disorder may receive replacement therapy with a synthetic form of vasopressin known as desmopressin (DDAVP, 1-desamino-8-D-arginine vasopressin). Desmopressin may be taken orally, injected, or used as a nasal spray.
Individuals with partial CDI and residual vasopressin activity may be treated with other drugs such as hydrochlorothiazide. Infants with diabetes insipidus are particularly problematic and may be treated by diluting the formula with water and with hydrochlorothiazide. DDAVP must be used with caution in this age group since infants have an obligate liquid intake to provide adequate calories for growth.
In cases of hereditary CDI, genetic counseling may be of benefit for affected individuals and their families. Other treatment is symptomatic and supportive.
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Contact for additional information about central diabetes insipidus:
Thomas A. Wilson, MD
Professor of Pediatrics
Chief, Pediatric Endocrinology
Stony Brook University Medical Center
Stony Brook, NY 11794-8111
Email: [email protected]stonybrookmedicine.edu
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