Central diabetes insipidus: what is it, symptoms, treatment, prognosis

What is central diabetes insipidus?

Central diabetes insipidus (abbr. CND) is a rare condition characterized by excessive thirst (polydipsia) and excessive urination (polyuria). The disease is not associated with a more common diabetes mellitusin which the body does not make or use insulin properly.

CDI is a clear disorder caused by a total or partial deficiency of arginine-vasopressin (AVP), which is required by the kidneys to control water balance in the body. If patients do not receive water, dehydration can occur. More serious symptoms may develop over time, including confusion and loss of mind, associated with dehydration and increased serum sodium concentration (hypertensive dehydration). CND can be caused by any condition that affects the production, transport, or release of vasopressin. CDI can be hereditary or acquired.

Signs and symptoms

In central diabetes insipidus, symptoms can develop over time or suddenly and can affect people of any age. CND is characterized by excessive thirst (polydipsia) and excessive urination (polyuria) even at night (nocturia). The severity and progression of the disease varies from case to case. Some people may have a severe form of the disorder (complete CNI) with little or no vasopressin activity. Others may have a mild form of the disorder (partial CND) with residual vasopressin activity.

Without the appropriate secretion of arginine-vasopressin, people with central diabetes insipidus cannot concentrate urine by absorbing water in the kidneys. This leads to the obligatory excessive excretion of not yet concentrated diluted urine. Consequently, people should drink excessive amounts of water to prevent dehydration. In response to thirst, sufferers can drink several gallons of water a day. If affected people are deprived of water for an extended period of time, rapid dehydration will occur. The thirst can be strong enough to wake people up from sleep.

Children may experience additional symptoms, including irritability, lethargy, vomiting, constipation and fever. If left untreated, repeated episodes of dehydration can lead to seizures, brain damage, developmental delays, and physical and mental retardation. However, with proper diagnosis and timely treatment, the intellect and further development of children is usually restored if there are no more global problems in the development of the brain. Affected children may develop urinary incontinence (enuresis), fatigue, weight loss, and stunted growth.

People with CNI are at risk for dehydration and cardiovascular symptoms, including irregular heartbeat, fever, dry skin and mucous membranes, confusion, epilepsy, changes in consciousness and, possibly, to whom. In adults, orthostatic hypotension, a condition in which blood pressure drops sharply when standing or sitting, can develop. Orthostatic hypotension can lead to dizziness or short-term loss of consciousness (syncope).

Causes of CDI

CND is caused by partial or complete deficiency of 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 about one third of cases, a specific cause cannot be identified (idiopathic) and may be of autoimmune etiology.

The hypothalamus is the part of the brain that acts as a connection between the brain and the endocrine system. The hypothalamus releases neurohormones that affect the secretion of other hormones, such as those that help with regulation of various metabolic processes, growth, reproductive function and autonomic functions organism. One of the substances secreted by the hypothalamus is vasopressin, which travels along nerve fibers to the back of the pituitary gland.

The pituitary gland 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 (neurohypophyseal region), which stores hormones and eventually releases them into the bloodstream. After the hypothalamus produces vasopressin, the hormone travels to the pituitary gland and accumulates in the neurophysis. Ultimately, vasopressin enters the bloodstream as needed by the body. The vasopressin then travels to the kidneys, where it binds to receptor proteins on the surface of certain kidney cells, initiating the process through which the kidneys absorb water into the body. Without the proper level of vasopressin, water is not absorbed and is lost during urination.

Damage to the hypothalamus, pituitary gland, or the junction between the hypothalamus and the pituitary gland (pituitary stalk) can disrupt making, transporting, storing or releasing vasopressin, which in turn impairs the body's ability conserve water. Such damage can result from:

• injury caused by an accident or surgery (such as surgery to remove a tumor in an area);
• various infections;
• tumors such as craniopharyngioma or germinoma;
• a rare disease known as Langerhans cell histiocytosis (PCH);
• various inflammatory, vascular or granulomatous diseases.

In rare cases, CND can be inherited as autosomal dominant trait. Genetic diseases are defined by a combination of genes for a specific trait that are found on chromosomes received from the father and mother. Dominant genetic disorders occur when only one copy of an abnormal gene is needed for a disease to appear. The abnormal gene can be inherited from either parent, or it can be the result of a new mutation (gene change) in the affected person. The risk of passing the abnormal gene from the affected parent to the offspring is 50% with every pregnancy, regardless of the sex of the child. Even more rare is autosomal recessive inheritance, in which none of the parents is susceptible to the disease, but each of them carries an abnormal gene, which, when passed on to offspring, leads to the disease.

Scientists have found that some cases of hereditary CNI are caused by abnormalities or changes (mutations) in the arginine-vasopressin gene (AVP / AVP). Mutations in the AVP gene interfere with 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 of each person. Human cells usually have 46 chromosomes. Pairs of human chromosomes are numbered 1 through 22, and the sex chromosomes are labeled X and Y. Men have one X and one Y chromosome, while women have two X chromosomes. Each chromosome has a short arm, labeled "p", and a long arm, labeled "q". Chromosomes are further subdivided into many numbered bands. For example, "chromosome 11p13" refers to lane 13 on the short arm of chromosome 11. The numbered stripes indicate the location of the thousands of genes present on each chromosome.

Researchers believe that some cases of idiopathic CND may be caused by autoimmune factors. Autoimmune Disorders arise when the body's natural defense against "alien" or invading organisms (viruses, bacteria), i.e. the immune system begins to attack healthy tissue for unknown reasons. In central diabetes insipidus, the body produces antibodies or lymphocytes that attack cells that secrete vasopressin.

CDI can also occur as part of a larger syndrome or disorder, including Wolfram syndrome or septo-optic dysplasia (de Morsier syndrome).

Affected populations

CDI affects men and women in equal numbers and can occur at any age. Onset is more common between the ages of 10 and 20. Hereditary CND is extremely rare, with fewer than 100 cases reported in the medical literature. It is estimated that 1 out of every 25,000 people has CMD.

Diagnostics of the central nervous system

The diagnosis of CND can be suspected based on the identification of characteristic signs, in particular excessive thirst and excessive urination. A thorough clinical assessment, a detailed medical history, and various special tests can be used to confirm the diagnosis. Doctors may take blood and urine samples to determine the salt and sugar concentration in these samples. The ratio of these substances to water in blood or urine is known as osmolality. People with CNI have high blood osmolality and low urine osmolality. Urine osmolality can be assessed by specific gravity, which is low in untreated diabetes insipidus.

Additional research may be needed to confirm the diagnosis or rule out other causes of diabetes insipidus. The analysis of vasopressin in blood is problematic because it is unstable and has a short half-life. The copeptin secreted by vasopressin is more stable. Hence, it provides a surrogate marker for vasopressin secretion. Patients may also receive a diagnostic injection of the arginine-vasopressin hormone or a vasopressin analogue such as DDAVP (see section 4.4). below) to determine the kidney response. People with another form of diabetes insipidus (i.e., nephrogenic diabetes insipidus / NID) do not respond to vasopressin supplementation because in NID the kidneys are resistant to the effects of vasopressin. Conversely, patients with CNI respond to vasopressin administration.

Some patients may need an additional test, known as a water deprivation test, to confirm the diagnosis. During this test, patients cannot ingest any liquids and can only eat dry foods for a specified 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 the secretion of vasopressin, which can be assessed by measuring the concentration of copeptin or urine concentration. Serum vasopressin levels can also be measured. The study will monitor body weight and vital signs to prevent excessive dehydration. This test can be used to distinguish between different causes of diabetes insipidus.

Some patients will need x-rays, including computed tomography (CT) or magnetic resonance imaging (MRI) to rule out brain tumors that can affect the pituitary gland, a potential cause of CDI. A common occurrence on MRI in children with central diabetes insipidus is the absence of A "light spot" at the back of the saddle, which is believed to be neurons containing vasopressin.

Symptomatic Disorders

Symptoms of the following disorders may be similar to those of CNI. Comparisons can be useful for differential diagnosis.

• Nephrogenic diabetes insipidus (NID) is a rare kidney disease that can be acquired or hereditary. NID is caused by complete or partial renal resistance to arginine-vasopressin (AVP / AVP). In this situation, the problem is not a defect in the synthesis or secretion of vasopressin, but the inability of the kidneys to respond to the secreted vasopressin. NPD causes chronic excessive thirst (polydipsia), excessive urine production (polyuria), and potentially dehydration. If left untreated, repeated episodes of severe dehydration can develop, eventually leading to serious complications. Most cases of hereditary NID disease are inherited as a recessive trait. Rare cases are inherited as an autosomal recessive or dominant trait. Two different genes have been identified that cause hereditary NDI: gene AVPR2 which encodes the vasopressin receptor and gene AQP2, encoding equaporin, which facilitates the transport of water and their reabsorption in the kidneys. NDI can also be acquired during life as a result of drug use (such as lithium therapy), kidney disease, ureteral obstruction, and long-term metabolic imbalances such as low blood potassium (hypokalemia) or high blood calcium (hypercalcemia).
• Diabetes (insulin-dependent diabetes) is a common condition in which the body does not produce enough insulin or is unable to properly use the available insulin. Consequently, the body is unable to properly transport glucose into the cells of the body. The disorder has a different etiology: genetic and environmental. Although the most obvious symptoms tend to be excessive thirst and urination, diabetes is not associated with diabetes insipidus and therefore treatments are different.
• Primary psychogenic polydipsia - a rare condition in which people drink excessive amounts of water in the absence of any normal stimulus for thirst. Affected people will produce excessive amounts of urine (polyuria) because they drink excessive amounts of water, not because they cannot concentrate urine. In response to excessive water intake, their pituitary gland secretes less vasopressin. Primary psychogenic polydipsia can potentially cause water toxicity, a condition that can cause serious complications. Some cases of primary psychogenic polydyspsia occur as part of a mental illness. In other cases, the cause is unknown.

Treatment of central diabetes insipidus

Ensuring proper fluid intake and reducing urine production is essential. Specific treatments for central diabetes insipidus include the administration of certain medications. Specific therapy varies depending on the severity of the vasopressin deficiency. Individuals with severe disorder may receive replacement therapy with a synthetic form of vasopressin known as desmopressin (DDAVP, 1-deamino-8-D-arginine vasopressin).

Desmopressin can be taken orally, by injection, or as a nasal spray.

Patients with partial CDI and residual vasopressin activity may be treated with other drugs such as hydrochlorothiazide. Children with diabetes insipidus are especially problematic and can be treated by diluting water and hydrochlorothiazide. Desmopressin should be used with caution in this age group as children need to consume fluids to get adequate calories for growth.

In cases of hereditary CDI, genetic counseling will be helpful for affected individuals and their families. Other treatments are symptomatic and supportive.