Diabetes Insipidus (Robertson)

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Title: Diabetes Insipidus (Robertson)
Author: Robertson, Gary
Publisher: Endocrinology and Metabolism Clinics of North America
Date Published: September 01, 1995
Reference Number: 55
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Diabetes insipidus, characterized by the excretion of copious volumes of unconcentrated urine, results from a deficiency in the action of the antidiuretic hormone arginine vasopressin and can be caused by any of four fundamentally different defects, including impaired secretion (neurohypophyseal diabetes insipidus), impaired renal response (nephrogenic diabetes insipidus), excessive fluid intake (primary polydipsia), or increased metabolism of the hormone (gestational diabetes insipidus). Differentiation between their causes, pathophysiology, and treatment methods is essential for effective management and is best achieved by a combination of hormonal, clinical, and neuroradiologic observations. Understanding of the genetic forms has advanced greatly and may soon lead to improved methods of prevention, diagnosis, and treatment.

This translation by the NDI Foundation is to assist the lay reader. To provide a clear, accessible interpretation of the original article, we eliminated or simplified some technical detail and complicated scientific language. We concentrated our translation on those aspects of the article dealing directly with NDI. The NDI Foundation thanks the researchers for their work toward understanding and more effectively treating this disorder.
© Copyright NDI Foundation 2007 (JC)

Diabetes insipidus (DI) is characterized by the excretion of abnormally large volumes of dilute urine. Dilute urine is urine that has a low solute-to-solvent ratio. Solute is the more solid part of a solution, e.g., the salt in salt water. Solvent is the liquid part of a solution, e.g., the water in salt water. DI is distinguished from uncontrolled diabetes mellitus by the absence of glucose in the urine and by a normal solute excretion rate.

Symptoms of DI include polydipsia (chronic, excessive thirst and increased fluid intake) and polyuria (chronic, excessive urination). Polyuria extends into the sleeping hours, interrupting sleep and leading, in children, to bedwetting. There are four types of DI:

  1. Neurohypophyseal DI, which is caused by a deficiency of the antidiuretic hormone, arginine vasopressin (AVP). This is the hormone that tells the kidneys to concentrate urine, a process which leads to normal water balance in the body.
  2. Nephrogenic DI, which occurs when there is enough AVP, but the kidneys do not respond to its message.
  3. Primary polydipsia, which occurs when there is an excessive intake of fluid and an accompanying underproduction of AVP. The excessive intake can be due to either a psychological disorder (psychologic primary polydipsia) or to a defect of the thirst mechanism (dipsogenic primary polydipsia).
  4. Gestational DI , which occurs when there is a deficiency of AVP caused by a marked increase in the ratio in which AVP is metabolized.

Each of these four types of DI has its own unique causes, mechanisms and therapeutic requirement.

Neurohypophyseal DI occurs when there is damage to the neurophysis, that part of the pituitary gland that produces AVP. This destruction may be a result of genetic disorders, or it may occur through diseases or accidents that damage the pituitary. The only clearly-defined genetic form of neurohypophyseal DI has been linked to mutations in the gene that synthesizes the substance from which AVP is formed. Think of the gene as having a huge number of bead-like parts that must be strung together in a precise order if the gene is to produce the proper protein. These parts can be rearranged in a number of ways that cause the gene to malfunction. Each faulty rearrangement is a different mutation.

Sometimes the neurophysis, though damaged or partially destroyed, can still secrete some AVP. The resulting neurohypophyseal DI is then called partial, as opposed to severe neurohypophyseal DI which occurs when the neurophysis can no longer produce any AVP. Both partial and severe forms are treated by giving patients synthetic AVP, which is safe and effective, but expensive. Other drugs such as chlorpropamide, clofibrute, or carbamazepine are also used. Of these, chlorpropamide is the most effective.

Nephrogenic DI is primarily caused by an abnormality in the innermost part of the kidney (the medulla) or in the little tubes in the kidney that help filter bodily fluids. These abnormalities may be genetic, acquired, or idiopathic (arising from unknown origins). But in most cases, the result is that the kidney cannot respond to the hormonal message of AVP. The most common cause of acquired nephrogenic DI is use of the drug lithium for treatment of certain psychological disorders. Other drugs can cause this form of DI, as can electrolyte disorders such as too little potassium or too much calcium in the blood. In most cases, once the drug is discontinued (unless lithium has been used long-term) or the electrolyte disorder is balanced, the nephrogenic DI can markedly improve and often resolve completely. This is not the case in the inherited form of nephrogenic DI.

The most common inherited form of nephrogenic DI is linked to mutations of the V2 receptor gene on the X chromosome. This gene produces the V2 receptor, the molecular structure that receives the message of AVP. When the V2 receptor can't bind with AVP, it means the kidneys can't concentrate urine, which means they can't balance body water and the symptoms of nephrogenic DI ensue. These symptoms may be expressed as early as the first week of life and must be diagnosed and treated early so as to avoid repeated bouts of dehydration and the damage, both physical and mental, that could ensue.

The other form of inherited nephrogenic DI occurs through mutations of the gene that produces aquaporin-2 (AQP2), a membrane protein that transports water through kidney cell membranes to help balance body water. There are many different types and locations of mutations that can produce the defective genes, whether in the V2 receptor gene or the AQP2 gene. Nephrogenic DI can be treated but, as yet, not cured. Nephrogenic DI patients do not respond to synthetic AVP, but adhering to a low-sodium diet and taking chlorothiazide, amiloride or indomethacin can reduce the patient's polyuria.

Psychologic primary polydipsia usually is acquired as a late manifestation of chronic schizophrenia. Dipsogenic polydipsia may sometimes be caused by diseases, injuries or drugs, but most of the instances in this category spring from unknown origins. In both forms of polydipsia, the person drinks far more water than is required. This excess causes a small reduction in the amount of AVP circulating in the body. Since in both forms of primary polydipsia the patient has adequate amounts of AVP and the kidney can respond to it, giving a patient drugs to abolish the polyuria could lead to water intoxication -- too much water in the system. There is no known pharmacological treatment for this form of DI.

During pregnancy, there is a marked increase in the metabolism of AVP. In some women, this is enough to degrade AVP to the point where DI is induced, resulting in gestational DI (though initial research suggests there must be a concomitant slight impairment in the capacity to secrete AVP for this form of DI to occur). Delivery of the placenta usually results in a return to normal AVP metabolism and urinary volume over a two to three week period. If needed, synthetic AVP, specifically DDAVP, is the only safe and effective treatment.

In all forms of DI, the symptoms are similar and all are a little less manifest at night than during the day. Polyuria and polydipsia are present by definition in all the forms, yet distinguishing among them is fairly straightforward. If the patient has dilute urine along with significant dehydration that causes a net flow out of the cell then he or she doesn't have either form of primary polydipsia. Administering synthetic AVP differentiates neurohypophyseal from nephrogenic DI because the former will respond to the AVP and the latter will not. The simplest, least expensive, and most accurate way to distinguish among neurohypophyseal, nephrogenic, and primary polydipsia is to measure plasma AVP levels before and during a standard fluid deprivation test (where the patient is deprived of water for a set amount of time), then to match the AVP levels at each time with the concurrent plasma and urine concentration.

Another, much less reliable, diagnostic approach is to scan the brain using magnetic resonance to determine the presence or absence of the posterior pituitary "bright" spot. This spot is absent in most people with neurohypophyseal DI but usually present in those with nephrogenic DI or primary polydipsia.