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Last updated:
4/15/2024
Years published: 2007, 2012, 2015, 2024
NORD gratefully acknowledges Shana E. McCormack, MD, MTR, Scientific Director, Neuroendocrine Center, Children’s Hospital of Philadelphia; Associate Professor of Pediatrics, Perelman School of Medicine at the University of Pennsylvania and Amy Wood, Raymond A. Wood Foundation, for assistance in the preparation of this report.
Summary
Arginine vasopressin deficiency (AVP-D) is a rare disorder characterized by excessive thirst (polydipsia) and excessive urination (polyuria). AVP-D is a distinct disorder caused by complete or partial deficiency of the hormone arginine vasopressin, or AVP. AVP is released from the posterior pituitary (part of the brain) when the body senses a need for more hydration. In response to AVP, the kidneys produce more concentrated urine and conserve water in the body. Individuals with AVP-D produce large quantities of dilute urine regardless of their hydration status. If they do not have access to water to drink, dehydration may occur. Eventually, more serious symptoms can develop including changes in consciousness and confusion associated with dehydration and elevation in blood sodium concentration (hypernatremic dehydration). Treatment of AVP-D with AVP analogues can also predispose to low blood sodium concentration (hyponatremia), can produce headache, malaise, fatigue, and when profound, seizure, coma, or even death. AVP-D may be caused by any condition that affects the creation, transport or release of AVP. AVP-D may be inherited or acquired. In some cases, no cause can be identified (idiopathic).
Introduction
Arginine vasopressin deficiency was formerly called central diabetes insipidus or CDI. The name of this disorder was changed to avoid medical errors related to confusion between central diabetes insipidus and diabetes mellitus. AVP-D is not related to the more common diabetes mellitus (sugar diabetes), in which the body does not produce or properly use insulin.
AVP-D symptoms may develop abruptly or more gradually over time and may occur at any age. Typically, individuals experience excessive urination (polyuria), even at night (nocturia), and as a result, excessive thirst (polydipsia). Some individuals with AVP-D lack thirst (adipsia) and are thus more vulnerable to dehydration from untreated AVP-D, and also hyponatremia from possible inadvertent excess fluid and synthetic AVP. The severity and progression of AVP-D varies from person to person. Some individuals may have a severe form of the disorder (complete AVP-D) with little or no AVP activity. Others may have a milder form of the disorder (partial AVP-D) with residual AVP activity.
Without appropriate AVP secretion, individuals with AVP-D are unable to concentrate the urine by reabsorbing water in the kidneys. This results in excessive production of dilute urine. Consequently, individuals must drink excessively to prevent dehydration. In response to thirst, affected individuals may drink copious quantities of water each day. If affected individuals are deprived of water to drink, dehydration can develop rapidly. Thirst cravings can be strong enough to awaken people from sleep.
Infants are unable to express thirst or independently seek water, thus their symptoms are more related to developing dehydration and high sodium levels in the blood. These include 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 intellectual disability. However, with proper diagnosis and prompt treatment, neurologic development can be preserved unless there are underlying associated problems in the brain (e.g., congenital anatomic abnormalities, tumors) that jeopardize these processes. Older children may also have bedwetting (enuresis), fatigue, weight loss and growth impairments, the latter because they drink so much water that they are unable to eat enough to achieve sufficient nutrition.
Individuals with AVP-D are at risk of developing dehydration and cardiovascular symptoms from electrolyte abnormalities including abnormal heart rhythms. They can also experience fever, dry skin and mucous membranes, confusion, seizures and alterations in consciousness. Symptoms can even potentially progress to lethargy and coma. Individuals with AVP-D may also develop orthostatic hypotension, a condition in which there is a substantial decrease in blood pressure upon standing or sitting. Orthostatic hypotension can result in dizziness or momentary loss of consciousness (syncope). Treatment of AVP-D with fluids and synthetic AVP can make individuals vulnerable to low sodium levels (hyponatremia), which has non-specific symptoms, including headache, fatigue and nausea. When severe, hyponatremia can lead to seizures or coma, and can even be fatal. Rapid correction of sodium concentration from either extreme can also lead to serious neurologic injury or death, thus treatment must be carefully monitored.
AVP-D is caused by partial or complete deficiency of the antidiuretic hormone, AVP. This deficiency usually results from damage to the hypothalamus or pituitary gland, often from a tumor (or surgical resection of that tumor) affecting these regions. In extremely rare cases, AVP deficiency is caused by a gene change (variant) that is inherited in an autosomal dominant or autosomal recessive pattern. In a minority of individuals, no specific cause can be identified (idiopathic AVP-D). There is speculation that there may be an autoimmune contribution. Finally, some medications, including a subset of anesthetic medications used in the intensive care unit, and novel anti-tumor therapies such as immune check-point inhibitors, can also cause AVP-D.
The hypothalamus is a portion of the brain that acts as a link between the brain and the endocrine system. The hypothalamus releases neuro-hormones that in turn influence the secretion of other endocrine hormones that regulate growth, reproduction, metabolism, stress and autonomic function. One of the substances secreted by the hypothalamus is AVP, which travels via nerve fibers to the posterior pituitary gland from where it can be secreted into the circulation.
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. The posterior lobe of the pituitary gland is known as the neurohypophysis (neurohypophsyeal region), which stores hormones and eventually secretes them into the bloodstream. After the hypothalamus produces AVP, the hormone travels to the pituitary gland and is stored in the neurohypophysis. AVP is eventually released into the bloodstream as needed by the body. AVP 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 AVP, water is not reabsorbed and is lost through urination.
Damage to the hypothalamus, pituitary gland or the connection between the hypothalamus and pituitary gland (the 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 other inflammatory, vascular, or granulomatous diseases.
Some cases of inherited AVP-D are caused by disease-causing variants in the arginine vasopressin (AVP) gene. These variants impair the production (synthesis) or secretion of vasopressin.
In rare cases, AVP-D may be inherited in an autosomal dominant pattern. Dominant genetic disorders occur when having only a single copy of a disease-causing gene variant is sufficient to cause the disease. The gene variant can be inherited from either parent or can be the result of a new (de novo) changed gene in the affected individual. The risk of passing the gene variant from an affected parent to a child is 50% for each pregnancy. The risk is the same for males and females.
Even rarer is an autosomal recessive mode of inheritance. Recessive genetic disorders occur when an individual inherits a disease-causing gene variant from each parent. If an individual receives one working copy of the gene and one disease-causing gene variant, the person will be a carrier for the disease, but usually will not show symptoms. The risk for two carrier parents to both pass the gene variant and have an affected child is 25% with each pregnancy. The risk of having a child who is a carrier like the parents is 50% with each pregnancy. The chance for a child to receive working copies of genes from both parents is 25%. The risk is the same for males and females.
Researchers believe that some cases of idiopathic AVP-D 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 AVP-D, the body produces antibodies or lymphocytes that attack cells that secrete vasopressin. Autoimmunity also appears to explain the AVP-D that can occur in response to administration of some anti-cancer therapies like immune checkpoint inhibitors. Several other medications have been shown to lead to AVP-D. In the ICU, multiple agents (e.g., dexmedetomidine) have been implicated in non-autoimmune, transient AVP-D. The possibility of medication induced AVP-D should be considered in the appropriate clinical circumstances.
AVP-D may also occur as part of a clinical syndrome and/or genetic disorder, including, for example, septo-optic dysplasia or Wolfram syndrome. (For more information on these disorders, choose the specific disorder name as your search term in the Rare Disease Database.)
AVP-D can occur at any age and affects males and females in equal numbers. Onset is more common between the ages of 10 and 20 years. The inherited form of AVP-D is extremely rare. When considering all forms, AVP-D is estimated to occur in 1 out of every 25,000 individuals.
A diagnosis of AVP-D may be suspected based upon presentation with characteristic symptoms, 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 degree of overall concentration of blood or urine is known as osmolality. Individuals with untreated AVP-D tend to have a high osmolality in the blood and a low osmolality in the urine. The urine osmolality may be approximated by the urine specific gravity, which is low in AVP-D. Often, paired blood and urine samples after the longest usual interval without drinking are sufficient to make the diagnosis of disordered AVP activity (AVP-D or AVP-R). For safety reasons, i.e., to avoid clinically significant dehydration, fluid deprivation beyond the longest usual interval is not recommended in the outpatient setting.
Additional tests may be necessary to confirm a diagnosis or exclude other causes of AVP-D. Assay of vasopressin in the circulation is problematic since it is unstable and has a short half-life. AVP is produced from the processing a larger hormone precursor, pre-pro-AVP. Another fragment from pre-pro-AVP processing is copeptin, which is more stable than AVP. Therefore, copeptin provides a more readily detectable surrogate marker of AVP secretion. Affected individuals may also receive a diagnostic “test” dose of the hormone AVP or an analogue of vasopressin such as desmopressin (see below) to determine the kidney response. Individuals with AVP-R do not respond to AVP treatment because in AVP-R the kidneys are resistant to its effects. Conversely, individuals with AVP-D do respond to supplemental AVP.
In some individuals, additional testing may be required to confirm the diagnosis of AVP-D. One such test is a water deprivation test. 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 are taken to measure serum sodium concentration or osmolality and urine output, osmolality or specific gravity. Evolving dehydration in a controlled clinical environment provides a stimulus for AVP secretion which can be estimated by measuring copeptin concentrations and by the concentration of the urine. Body weight and vital signs are monitored to prevent excessive dehydration. This test may be used to distinguish between AVP-D and primary polydipsia. At the conclusion of the test, if the urine remains dilute despite dehydration, suggestive of AVP-D, a test dose of AVP or desmopressin can also be administered.
At least two additional provocative tests have also been developed and are sometimes used. First, administration of hypertonic saline leads to increased blood osmolality in much the same way that water deprivation does. This stimulus should lead to AVP secretion, and associated rise in copeptin, in individuals without AVP-D. In individuals without AVP-D or AVP-R, increased blood osmolality will also lead to concentration of urine. This test can be used to distinguish AVP-D (complete or partial) from primary polydipsia. Another test, arginine stimulation, typically produces a rise in blood copeptin in individuals without AVP-D and may be a simpler alternative. Identifying best practices for testing for AVP-D remains the focus of research. Notably, there may be assay-specific differences in copeptin that affect the translatability of proposed copeptin thresholds across studies and/or clinical settings.
Some individuals have brain imaging including computed tomography (CT scan) or magnetic resonance imaging (MRI) to rule out a structural problem (e.g., tumor, congenital abnormality) affecting the hypothalamus and/or pituitary gland, a potential cause of AVP-D. A common finding on MRI in children with AVP-D is absence of the “bright spot” in the posterior sella. The typical bright spot is thought to represent AVP containing neurons.
Treatment
Ensuring adequate, but not excessive, hydration and reducing disruptive thirst and urine output are essential. Optimizing quality of life is another important goal. Specific therapy varies depending upon the severity of AVP-D. Individuals with the complete 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 AVP-D and residual AVP-D activity may be allowed simply to drink water when they are thirsty. Rarely, they may be treated with other drugs such as hydrochlorothiazide to decrease urine output because this drug decreases urinary volume in people who have vasopressin deficiency. Infants with AVP-D are particularly challenging to treat since infants need liquid intake for adequate calories for growth, thus desmopressin must be used thoughtfully to avoid over-hydration and hyponatremia. Subcutaneous injectable and buccal formulations may allow more refined titration of demopressin doses. Infants are treated with low osmolality nutrition (breast milk is optimal if available) and may also require supplemental water. Hydrochlorothiazide can be used in infants to decrease urine output but can also lead to electrolyte abnormalities and may affect growth over time, so infants treated with this medication should be reassessed periodically, especially when they are requiring less liquid for nutrition (i.e., when they are taking solid foods) to see if they are candidates for desmopressin.
All individuals with AVP-D require thoughtful management of fluids, especially when ill. They also need easy access to blood sodium testing, again, especially when they are ill and may have varying needs, or difficulty with drinking fluids and/or taking medications. Individuals with intact thirst should drink to thirst, have access to water, and should not be encouraged to drink beyond thirst. Individuals with adipsic AVP-D (i.e., lacking intact thirst) may have an individualized fluid and desmopressin prescription that is adjusted if there is evidence of over- or under-hydration. In-home point of care sodium testing is not widely available currently, but strategies to achieve this type of actionable real-time monitoring are the focus of ongoing research.
In cases of hereditary AVP-D, genetic counseling is recommended for affected individuals and their families. Other treatment is symptomatic and supportive.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
Toll free: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov
Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/
For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com
For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/
JOURNAL ARTICLES
Angelousi A, Alexandraki KI, Mytareli C, Grossman AB, Kaltsas G. New developments and concepts in the diagnosis and management of diabetes insipidus (AVP-deficiency and resistance). J Neuroendocrinol. 2023;35(1):e13233. Epub 2023/01/24. doi: 10.1111/jne.13233. PubMed PMID: 36683321.
Boot C. The laboratory investigation of diabetes insipidus: A review. Ann Clin Biochem. 2023:45632231154391. Epub 2023/01/19. doi: 10.1177/00045632231154391. PubMed PMID: 36650746.
Kraus MB, Leuzinger K, Reynolds E, Gallo de Moraes A, Smith J, Sharpe EE, Quillen J, Kosiorek H, Harbell MW. Diabetes insipidus related to sedation in the intensive care unit: A review of the literature. J Crit Care. 2023;75:154233. Epub 20230202. doi: 10.1016/j.jcrc.2022.154233. PubMed PMID: 36738631.
Pedersen AN, Krogh J, Andreassen M, Rasmussen AK. Desmopressin dose requirements in adults with congenital and acquired central diabetes insipidus. Horm Metab Res. 2023. Epub 20231025. doi: 10.1055/a-2198-7207. PubMed PMID: 37879354.
Statlender L, Fishman G, Hellerman M, Kagan I, Bendavid I, Gorfil D, Kaptzon S, Singer P. Transient diabetes insipidus in critically ill COVID19 patients. J Crit Care. 2023;74:154211. Epub 2023/01/12. doi: 10.1016/j.jcrc.2022.154211. PubMed PMID: 36630859; PMCID: PMC9828890.
Barnabei A, Strigari L, Corsello A, Paragliola RM, Iannantuono GM, Salvatori R, Corsello SM, Torino F. Grading central diabetes insipidus induced byiImmune checkpoint inhibitors: a challenging task. Front Endocrinol (Lausanne). 2022;13:840971. Epub 20220321. doi: 10.3389/fendo.2022.840971. PubMed PMID: 35388297; PMCID: PMC8978963.
Iraqi HM, Pigarova E, Zacharieva S, Colao A, Baraf L, Tsoli M, Doknic M, Bitti SR, Giordano R, Barbot M, Akirov A, Witek P, Serebro M, Auer MK, Toth M, Shimon I. Idiopathic central diabetes insipidus in a large cohort of patients: the hypopituitarism ENEA rare observational (HEROS) study. Pituitary. 2022. Epub 2022/10/20. doi: 10.1007/s11102-022-01277-1. PubMed PMID: 36260240.
Pogacar PR, Mahnke S, Rivkees SA. Management of central diabetes insipidus in infancy with low renal solute load formula and chlorothiazide. Curr Opin Pediatr. 2000;12(4):405-11. PubMed PMID: 10943825.
Christ-Crain M, Bichet DG, Fenske WK, Goldman MB, Rittig S, Verbalis JG, Verkman AS. Diabetes insipidus. Nat Rev Dis Primers. 2019;5(1):54. Epub 2019/08/10. doi: 10.1038/s41572-019-0103-2. PubMed PMID: 31395885.
Saldarriaga C, Lyssikatos C, Belyavskaya E, Keil M, Chittiboina P, Sinaii N, Stratakis CA, Lodish M. Postoperative diabetes insipidus and hyponatremia in children after transsphenoidal surgery for adrenocorticotropin hormone and growth hormone secreting adenomas. The Journal of Pediatrics. 2018. doi: 10.1016/j.jpeds.2017.11.042. PubMed PMID: 29395172.
Dabrowski E, Kadakia R, Zimmerman D. Diabetes insipidus in infants and children. Best practice & research. Clinical Endocrinology & Metabolism. 2016;30(2):317-28. doi: 10.1016/j.beem.2016.02.006. PubMed PMID: 27156767.
Eisenberg Y, Frohman LA. Adipsic diabetes insipidus: a review. Endocr Pract. 2016;22(1):76-83. doi: 10.4158/EP15940.RA. PubMed PMID: 26401579.
Gleeson H, Bonfield A, Hackett E, Crasto W. Concerns about the safety of patients with diabetes insipidus admitted to hospital. Clin Endocrinol (Oxf). 2016;84(6):950-1. Epub 2016/01/30. doi: 10.1111/cen.13028. PubMed PMID: 26824191.
Smego AR, Backeljauw P, Gutmark-Little I. Buccally administered intranasal desmopressin acetate for the treatment of neurogenic diabetes insipidus iniInfancy. The Journal of Clinical Endocrinology and Metabolism. 2016;101(5):2084-8. Epub 2016/03/25. doi: 10.1210/jc.2016-1157. PubMed PMID: 27011115.
Bockenhauer D, Bichet DG. Pathophysiology, diagnosis and management of nephrogenic diabetes insipidus. Nat Rev Nephrol. 2015;11(10):576-88. doi: 10.1038/nrneph.2015.89. PubMed PMID: 26077742.
Rivkees SA, Dunbar N, Wilson TA. The management of central diabetes insipidus in infancy: desmopressin, low renal solute load formula, thiazide diuretics. J Pediatr Endocrinol Metab. 2007;20(4):459-69. PubMed PMID: 17550208.
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