Version May 2024
INTRODUCTION — Arginine vasopressin deficiency (AVP-D), previously called central diabetes insipidus [1], is characterized by decreased release of arginine vasopressin (AVP), also known as antidiuretic hormone (ADH), resulting in variable degrees of polyuria. Lack of AVP can be caused by disorders that act at one or more of the sites involved in AVP synthesis and secretion: the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract [2]. By contrast, damage to the neurohypophysis below the median eminence or to the posterior pituitary generally causes no or only transient polyuria, depending upon the chronicity of the damage, because AVP synthesized in the hypothalamus can still be secreted into the systemic circulation via the pituitary portal capillaries in the median eminence [2]. (See "Hypothalamic-pituitary axis".)
The etiologies, clinical manifestations, and postdiagnostic evaluation of AVP-D are reviewed in this topic. Related issues are discussed separately:
●Evaluation of patients with polyuria and diagnosis of AVP-D (see "Evaluation of patients with polyuria")
●Treatment of AVP-D (see "Arginine vasopressin deficiency (central diabetes insipidus): Treatment")
EPIDEMIOLOGY — AVP-D is a rare disorder, with a reported prevalence of 1 in 25,000 individuals [3]. Most cases are acquired; AVP-D is attributable to genetic causes in fewer than 5 percent of patients. The prevalence of AVP-D is similar in females and males. This contrasts with arginine vasopressin V2 resistance (AVP-R, formerly called nephrogenic diabetes insipidus), which is often X-linked and occurs predominantly in males.
PATHOPHYSIOLOGY — AVP-D is caused by the inability of the neurohypophysis to synthesize and/or secrete AVP in response to increased plasma osmolality (figure 1). Although AVP-D can be inherited as an autosomal dominant disease or caused by developmental abnormalities, most cases are acquired (table 1).
The neurohypophysis consists of the complete neuronal unit responsible for synthesizing and secreting AVP, which includes the hypothalamic cell bodies in the supraoptic and paraventricular nuclei that synthesize AVP, the AVP axons coursing through the pituitary stalk, and the posterior pituitary, where the neuron terminals secrete AVP into the circulation.
Damage or dysfunction of any part of the neurohypophysis, if sufficiently severe, can cause AVP-D. Plasma levels of AVP (and of copeptin, which is a cleavage product of the AVP prohormone) are undetectable in complete AVP-D and inappropriately low for the plasma osmolality in partial AVP-D.
Normal function of only 10 to 15 percent of the AVP-producing neurons is generally sufficient to secrete enough AVP to prevent symptoms. However, loss of a small proportion of the remaining functioning neurons can produce an increased urine output and symptomatic polyuria. Deficient AVP release leads to diminished insertion of aquaporin 2 water channels (ie, aquaporin 2) into the luminal membrane of the collecting duct (figure 2). This in turn impairs the ability of the kidney to concentrate the urine and leads to excretion of a large volume of hypotonic (ie, dilute) urine, thereby increasing the plasma osmolality. The increase in plasma osmolality stimulates thirst and polydipsia.
AVP-D may also result from osmoreceptor dysfunction. In such patients, the neurohypophysis is intact, but the osmoreceptors in the anterior hypothalamus that are responsible for detecting a rise in plasma osmolality are damaged. As a result, stimulation of AVP secretion is diminished, and the patient becomes symptomatic due to deficient AVP secretion despite normal amounts of AVP production. However, in contrast to AVP-D from damage to the neurohypophysis, osmoreceptor dysfunction does not result in polydipsia, since the osmoreceptors are necessary for osmotically stimulated thirst as well as AVP secretion. This results in a disorder called "adipsic AVP-D" (or adipsic diabetes insipidus). The combination of insufficient AVP secretion and lack of polydipsia (due to a diminished thirst response) in patients with adipsic AVP-D typically leads to hypernatremia. However, when baroreceptors are stimulated by hypovolemia or hypotension, AVP stored in the posterior pituitary is secreted and the urine becomes concentrated, obscuring the diagnosis of AVP-D. In addition, some patients with adipsic AVP-D release a constant, albeit low, amount of AVP that may result in hyponatremia if affected patients substantially increase their water intake [4].
ETIOLOGY — AVP-D may be acquired or congenital (table 1).
Acquired causes — Acquired AVP-D accounts for the majority of cases. The most common acquired causes of AVP-D are autoimmune neurohypophysitis, primary or secondary tumors, infiltrative diseases (such as Langerhans cell histiocytosis and sarcoidosis) [5], neurosurgery, and head trauma [2,5-8]. The prevalence of the various etiologies of AVP-D varies by age at the time of presentation (eg, child versus adult) and the clinical setting at the time of presentation; however, regardless of the setting, genetic and developmental or congenital causes account for less than 5 to 6 percent of all reported cases.
Neurosurgery or trauma — AVP-D can be induced by neurosurgery (usually in the sellar or suprasellar area) or by head trauma that damages the hypothalamus and posterior pituitary [9-13]. Less commonly, AVP-D has been reported after spine surgery involving traction of the spinal cord [14-16].
AVP-D is transient in most cases that are related to neurosurgery. The incidence of transient AVP-D in these patients varies with the extent of injury, ranging from 10 to 20 percent after transsphenoidal removal of an adenoma limited to the sella to as high as 60 to 80 percent after removal of large tumors that extend beyond the sella [17]. The incidence of postoperative AVP-D is lower with minimally invasive endoscopic pituitary surgery. In one survey, for example, transient AVP-D occurred in 5 percent of patients undergoing minimally invasive pituitary surgery and permanent AVP-D occurred in 1.5 percent [18]. A serum sodium concentration higher than 145 mEq/L within the first five postoperative days is associated with a higher likelihood of permanent AVP-D [19]. By contrast, patients with a serum sodium less than 145 mEq/L in the first five postoperative days will rarely, if ever, develop permanent AVP-D, thereby validating short postoperative inpatient stays with minimal risk of readmission in such patients.
Permanent postoperative AVP-D is uncommon; the incidence is less than 2 percent following resection of pituitary adenomas [18], but can be as high as 25 percent following resection of suprasellar tumors such as craniopharyngiomas [11,20,21]. This is in large part due to their suprasellar location and the greater corresponding risk of damage to the AVP cell bodies in the hypothalamus.
The development of AVP-D after traumatic brain injury (TBI) depends upon the severity of the injury. It has been reported in up to 50 percent of patients with moderate to severe TBI (defined as Glasgow Coma Score <13), but it is usually transient (table 2) [22]. Deceleration injuries are a common cause of AVP-D as they can cause a shearing of the pituitary stalk at the level of the diaphragm sella, which sometimes can be detected by magnetic resonance imaging (MRI). In addition, patients with basilar skull fractures should always be evaluated for possible accompanying AVP-D. AVP-D after mild TBI is uncommon.
If connections between the AVP cell bodies (in the hypothalamus) and nerve terminals (in the posterior pituitary gland) are severed by neurosurgery or trauma, a triphasic response develops in 3 to 5 percent of patients [6,11,23]. The first phase of the response, characterized by polyuria due to AVP-D, is followed three to six days later by the second phase, the syndrome of inappropriate antidiuresis (SIAD), which is caused by uncontrolled release of AVP into the circulation from the degenerating nerve terminals in the posterior pituitary gland. SIAD can last for five to seven days, and during this stage, excessive water intake can lead to hyponatremia. The third phase, marked by redevelopment of polyuria due to AVP-D, develops if more than 80 to 90 percent of AVP-producing neurons in the hypothalamus die because of retrograde degeneration.
A study of 1571 patients with pituitary adenomas of all types who underwent transsphenoidal surgery at the same center provides insight into the relative frequency of different AVP-related disorders [24]. Among these patients, 30 percent had microadenomas and 70 percent macroadenomas. The key findings were as follows:
●31 percent had immediate postoperative polyuria, 17 percent had polyuria on day 3, and 6 percent on day 7. Of these patients, 24 percent received one or more doses of exogenous desmopressin. After three months, only 0.9 percent were still receiving desmopressin or had polyuria.
●3.4 percent of patients had transient polyuria and then transient hyponatremia.
●1.1 percent had the full triphasic pattern of polyuria, hyponatremia, and then polyuria.
●5.2 percent had only transient hyponatremia, either within one to three days or five to ten days after surgery, which follows a time course analogous to the second phase of a triphasic response and is due to uncontrolled release of AVP from degenerating AVP nerve terminals in the posterior pituitary [25]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
Head trauma and neurosurgery, particularly clipping of an aneurysm of the anterior cerebral communicating artery, can also lead to adipsic AVP-D, with dysfunction of osmoreceptors, as described above [26].
Despite the relatively high frequency of AVP-D in patients undergoing neurosurgery, some cases of polyuria in this setting are not due to injury to the neurohypophysis [9]. Transient post-neurosurgery AVP-D may be due to anesthetic medications rather than anatomic injury [27]. More common causes of postoperative polyuria include excretion of excess fluid administered during surgery [28], an osmotic diuresis induced by mannitol, or an osmotic diuresis caused by hyperglycemia (resulting from glucocorticoid administration). These conditions can be differentiated from AVP-D by carefully following the serum sodium concentration and urine osmolality in response to water restriction. (See "Evaluation of patients with polyuria".)
Autoimmune neurohypophysitis — Approximately 30 to 50 percent of cases of nontraumatic AVP-D are believed to be associated with destruction of the hormone-secreting cells in the hypothalamic nuclei. It has been suggested that an autoimmune process is involved in many, if not most, such patients [29-32]. Insight into the mechanism of autoimmunity in some individuals was provided by a longitudinal study evaluating the presence of cytoplasmic antibodies directed against vasopressin cells (Ab-positive) in patients with endocrine autoimmune diseases but initially without AVP-D [30]. Among almost 900 such patients, 9 that were Ab-positive and 139 Ab-negative controls were prospectively followed. At four years, none of the controls developed AVP-D. By comparison, four of the nine Ab-positive patients had partial AVP-D at study entry, and among the remaining five patients, three developed partial AVP-D and one developed complete AVP-D.
The prevalence of antibodies to AVP neurons, their association with other autoimmune diseases, and their correlation with radiologic features were evaluated in a study of 150 patients with AVP-D [31]. The disease was "idiopathic" in 43 percent, familial in 4 percent, granulomatous in 8 percent, and secondary to cranial trauma, tumor, or surgery in 45 percent. Antibodies to AVP neurons were found in approximately one-third of the patients with "idiopathic" AVP-D and in approximately one-quarter of patients with nonidiopathic disease. Antibody positivity was independently associated with younger age at disease onset in those with idiopathic AVP-D, a history of other autoimmune disease, or pituitary stalk thickening. The autoantigens involved in autoimmune neurohypophysitis have not yet been fully elucidated. However, autoantibodies to rabphilin-3A, a regulator of secretory vesicle trafficking, are found in many patients [33].
The autoimmune process is characterized by lymphocytic inflammation of the pituitary stalk and posterior pituitary [29]. This disease process is named lymphocytic infundibuloneurohypophysitis (LINH), and likely accounts for the majority of autoimmune AVP-D cases [34]. Characteristically, the pituitary stalk inflammation resolves after destruction of the target neurons. MRI, if performed early in the course, often reveals thickening or enlargement of the pituitary stalk that increases over the initial one to two years and then regresses [35].
Other autoimmune mechanisms for AVP-D include immunoglobulin (Ig) G4-related syndrome, in which neurohypophysitis is only one manifestation of a multiorgan disease that can affect other endocrine glands [36-38], and granulomatosis with polyangiitis (GPA), a systemic disease characterized by necrotizing, small-vessel vasculitis, often associated with positive antineutrophil cytoplasmic antibodies (ANCA) [39]. In addition, AVP-D can occur in patients with autoimmune polyglandular syndrome type I, which results from a mutation of the autoimmune regulator gene (AIRE) [40]. Adipsic AVP-D in the absence of structural abnormalities is thought to be caused by autoantibodies to cells in the subfornical organ [41]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical manifestations and diagnosis of IgG4-related disease".)
Malignancy — Primary or secondary brain tumors (most often due to lung or breast cancer, leukemia, or lymphoma) can involve the hypothalamic-pituitary region and lead to AVP-D [8]. AVP-D can also be observed in myelodysplastic syndrome [42]. In some patients with metastatic disease, polyuria is the presenting symptom [8].
Intracranial germ cell tumors (IGCTs), broadly classified as germinomas or nongerminomatous (including mixed germ cell tumors, malignant teratomas, choriocarcinomas, embryonal carcinomas, and yolk sac tumors), have an annual incidence rate in the United States of 1.2 cases per million males and 0.4 cases per million females [43]. IGCTs occur most often in 10- to 19-year-old patients [44-46]. IGCTs most frequently develop in the pineal gland, followed by the suprasellar region within the pituitary stalk. The pituitary is the primary site in an estimated 8 percent of cases [47], and in one study, 11 percent of such tumors infiltrated the hypothalamus [48]. In a small study involving 24 patients with suprasellar IGCTs, 50 percent of the patients presented with AVP-D, 26 percent with growth hormone deficiency, 19 percent with central hypothyroidism, and 19 percent with central adrenal insufficiency.
AVP-D occurs rarely in patients with pituitary adenomas. Such lesions, located in the sella turcica, may damage the posterior pituitary, which is where AVP-containing neurosecretory granules are stored. However, AVP is synthesized in the cell bodies located in the hypothalamus. Gradual damage only to the nerve terminals located in the posterior pituitary does not prevent production of AVP. Because pituitary adenomas grow slowly, the secretory site for AVP can shift proximally, superior to the pituitary stalk and median eminence. Thus, if a pituitary lesion is noted in a patient with AVP-D, alternative diagnoses should be suspected, such as a craniopharyngioma (that involves the suprasellar region) [11,21], pituitary apoplexy, or a rapidly-growing metastatic lesion.
Meningiomas frequently involve the suprasellar region but rarely cause AVP-D because they are slow growing, which allows sufficient time for the site of AVP release to shift superior to the median eminence, similar to pituitary macroadenomas. One exception is the rare occurrence of meningiomas originating from the pituitary stalk, which have been associated with AVP-D [49].
Adipsic AVP-D rarely occurs as part of the ROHHADNET (rapid-onset obesity with hypoventilation, hypothalamic, autonomic dysregulation, and neural tumor) syndrome [50]. This has been reported predominantly in children, but no single tumor has been associated with the syndrome.
Infiltrative disorders — Patients with Langerhans cell histiocytosis (also called histiocytosis X and eosinophilic granuloma) are at particularly high risk for AVP-D due to hypothalamic-pituitary disease [5,51]. Up to 40 percent of patients become polyuric within the first four years, particularly if there is multisystem involvement and proptosis. In some cases, AVP-D can be the presenting feature of Langerhans cell histiocytosis. (See "Clinical manifestations, pathologic features, and diagnosis of Langerhans cell histiocytosis".)
A similar infiltrative disease can occur with sarcoidosis, which can also cause polyuria due to AVP V2 resistance (AVP-R) as a result of hypercalcemia or granulomatous interstitial nephritis; primary polydipsia can also contribute to polyuria in this disorder [52]. (See "Causes of hypopituitarism", section on 'Hypophysitis'.)
Vascular disorders — AVP-D has been reported in a variety of neurovascular disorders. Approximately 15 percent of patients who have subarachnoid hemorrhage develop acute AVP-D although hyponatremia is more common in this disorder [53]. The AVP-D is usually transient, and very few survivors of subarachnoid hemorrhage have permanent AVP-D.
Ischemic disorders rarely cause AVP-D since most ischemic strokes are unilateral and the AVP neuronal cell bodies of the neurohypophysis are bilateral. As noted above, loss of even 50 percent of AVP-producing neurons will not be sufficient to produce AVP-D. However, one important exception to this is infarction of the anterior wall of the hypothalamus, which may be a surgical complication of clipping anterior communicating artery aneurysms. Surgical damage to the perforating arteries of the anterior communicating artery and therefore infarction of the anterior hypothalamus, where osmoreceptors are situated, can cause adipsic AVP-D.
Infections — Infection is a rare cause of AVP-D. Several cases of AVP-D have been reported in association with acute bacterial meningitis caused by different bacteria [54]. In addition, AVP-D may occur with chronic tuberculous meningitis, in which it is usually a late manifestation of widespread disease [55]. The pathophysiology is assumed to be inflammation and gliosis that compresses the pituitary stalk, and other functions of the anterior pituitary may be affected.
Other acquired causes
●Hypoxic encephalopathy – Hypoxic encephalopathy or severe ischemia (as with cardiopulmonary arrest or shock) can lead to diminished AVP release [6,56]. The severity of this defect varies, ranging from mild and asymptomatic to marked polyuria. As an example, overt AVP-D is unusual in patients with Sheehan syndrome (postpartum hypopituitarism) even though AVP secretion is often subnormal [57]. The appearance of AVP-D in these patients is consistent with the occasional pathologic findings of scarring and atrophy in the supraoptic nuclei and posterior pituitary gland [58]. (See "Causes of hypopituitarism".)
●Idiopathic AVP-D – A large proportion of patients with AVP-D appear to have idiopathic disease. Such patients lack an identifiable cause of AVP-D (ie, there is no history of head trauma, neurosurgery, cerebrovascular event, infiltrative disorder, or malignancy). In addition, neuroimaging with MRI does not reveal any substantial abnormalities (except for thickening of the pituitary stalk and absence of a pituitary bright spot). Most such patients remain without an identifiable cause during long-term follow-up [59]. However, as noted above, autoimmune neurohypophysitis may account for a large proportion of "idiopathic" disease.
Anterior pituitary hormone deficiency, with decreased release of growth hormone, thyroid-stimulating hormone, and adrenocorticotropic hormone, also may be present or develop in patients with idiopathic AVP-D [7,60]. However, some patients who develop an anterior pituitary endocrinopathy years after the diagnosis of AVP-D may have a pituitary or suprasellar tumor or other generalized lesion, suggesting that the initial abnormality was due to an occult pathologic process [35,61,62]. As an example, in one study of 16 patients first diagnosed with idiopathic AVP-D, the detection of evolving gonadotropin deficiency in three individuals resulted in the diagnosis of pituitary or suprasellar germinomas 20, 6, and 3 years after the initial presentation [61]. Thus, patients diagnosed with idiopathic AVP-D should generally undergo regular endocrine follow-up. (See "Diagnostic testing for hypopituitarism".)
●Post–supraventricular tachycardia – Transient polyuria is occasionally seen after correction of a supraventricular tachycardia [63,64]. Both a water diuresis and a natriuresis may be seen, due respectively to decreased secretion of AVP and to increased release of atrial natriuretic peptide. These humoral changes may be mediated by increases in left atrial and systemic pressure, thereby activating local volume receptors.
●Anorexia nervosa – AVP release is often subnormal or erratic in patients with anorexia nervosa, presumably due to the cerebral dysfunction [65]. This defect is relatively mild in most cases, and polyuria, when present, is due mostly to a primary increase in thirst or habitual polydipsia.
●Brain death – In various studies, AVP-D occurs in 30 to 80 percent of brain dead individuals, with a higher incidence in adults compared with children [66,67]. In those who are potential organ donors, treatment of AVP-D may be pursued although there is not firm evidence that treating the AVP-D maintains the quality of donor organs [68]. Brain dead individuals with AVP-D often have coexistent anterior pituitary deficiency, especially secondary adrenal insufficiency that should also be treated if organ donation is anticipated.
●Drugs – AVP-D has rarely been reported in patients treated with ipilimumab and in those exposed to toluene [26,69,70]. Transient AVP-D has also been reported after discontinuation of vasopressin infused to treat hypotension [71].
Genetic or congenital causes — Several familial and congenital diseases are associated with AVP-D. These include familial AVP-D, Wolfram syndrome, proprotein convertase subtilisin/kexin type 1 (PCSK1) gene deficiency, and congenital diseases such as congenital hypopituitarism and septo-optic dysplasia.
Familial AVP-D — Familial AVP-D, also called familial neurohypophyseal diabetes insipidus, or FNDI (MIM 125700), is usually an autosomal dominant disease caused by mutations in the gene encoding AVP [72].
AVP and its corresponding carrier, neurophysin II, are synthesized as a composite precursor (pro-AVP) by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus [73]. The variants associated with familial AVP-D prevent the cleavage of pro-AVP, leading to its accumulation in the endoplasmic reticulum (ER) [74]; the retained mutant pro-AVP forms a complex with AVP produced by the unaffected allele. This complex is then degraded via ER-associated degradation [75].
This autosomal dominant form of AVP-D contrasts with congenital AVP deficiency that has been described in three families with autosomal recessive AVP-D. Two families bear a missense variation affecting the seventh amino acid of the AVP nonapeptide (p.Pro26Leu) [76,77], and four members of one family with two loops of inbreeding bear a large deletion involving the majority of the AVP gene as well as the intergenic region between the AVP and OXT genes [78]. Affected members have early-onset polyuria and hypernatremia, in contrast to the autosomal dominant disease mentioned above. The existence of this autosomal recessive, early onset AVP-D is important because it must be considered, along with congenital AVP-R, in the differential diagnosis of congenital polyuria and dehydration, and therapy for these disorders differ.
Other genetic and congenital causes
●Wolfram syndrome – The Wolfram or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is characterized by AVP-D, diabetes mellitus, optic atrophy, and deafness, with cognitive and psychiatric issues that can appear later in life [79]; it is inherited as an autosomal recessive trait with incomplete penetrance. The Wolfram syndrome is caused by at least two different genes: WFS1 and CISD2 [80]. Both encode ER proteins and seem to affect calcium homeostasis. Wolframin, the product of WFS1, is expressed in a number of tissues, including the pancreas [81] and brain supraoptic and paraventricular nuclei [82]. AVP-D in this disorder is due to loss of AVP-secreting neurons in the hypothalamus and impaired processing of AVP precursors [83].
Variations in WFS1 also predispose to type 2 diabetes mellitus [84]. WFS1 negatively regulates a key transcription factor involved in ER stress signaling, resulting in pancreatic beta cell death and possibly in magnocellular cell death, which could explain the AVP deficiency [85]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Wolfram syndrome'.)
●PCSK1 gene deficiency – The PCSK1 gene encodes a 753-amino acid precursor, preproPC1/3, which is processed in the ER into its proenzyme form, proPC1/3. ProPC1/3 is then modified by cleavage of its prodomain into active PC1/3 [86]. PC1/3 is involved in the processing of numerous digestive and hypothalamic prohormones, including AVP. More than 25 cases of PC1/3 deficiency have been reported in the literature; 30 percent were of Turkish origin [2,87]. All individuals had early and severe malabsorptive diarrhea, and approximately 80 percent had polyuria-polydipsia syndrome (before five years of age). Most had early-onset obesity. Various endocrine disorders were present, including growth hormone deficiency (44 percent), mild central hypothyroidism (56 percent), central hypogonadism (44 percent), central hypocortisolism (57 percent), and postprandial hypoglycemia (52 percent). A history of consanguinity was present in 83 percent [87].
●Congenital hypopituitarism – AVP-D has been described in patients with congenital hypopituitarism with or without ectopia of the posterior pituitary lobe [88-90]. The defects in posterior pituitary function in these disorders include symptomatic AVP-D, nocturia, reduced AVP release after osmotic challenge, and hypodipsia or polydipsia. These findings can be associated with isolated growth hormone deficiency or multiple anterior pituitary hormone deficiencies.
●Septo-optic dysplasia (SOD) – AVP-D can be seen in a number of congenital cerebral midline developmental abnormalities. As an example, SOD has been associated with defects in both anterior and posterior pituitary function [91,92]. SOD is a highly heterogeneous condition with phenotypes that include midline and forebrain abnormalities as well as optic nerve and pituitary hypoplasia. Most cases of SOD are sporadic, but familial cases have been described in association with mutations in genes for developmental transcription factors (such as HESX1) that are essential for normal forebrain/pituitary development [93]. Affected patients can have abnormal thirst as well as a defect in AVP secretion [92,94]. Monitoring of serum sodium in these patients is recommended once per week for one month and then, if stable, once every six months.
CLINICAL MANIFESTATIONS — Patients with untreated AVP-D typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia. Depending upon the specific cause of the AVP-D, patients may also have neurologic symptoms related to the underlying disorder, such as diplopia and headache [95].
The serum sodium concentration in untreated AVP-D is often in the high normal range, which is required to provide the ongoing stimulation of thirst to replace the urinary water losses [96]. Moderate to severe hypernatremia can develop when thirst is impaired or cannot be expressed or if there is no access to water. This occurs most commonly in infants and young children who cannot independently access free water, in patients with unrecognized AVP-D in the postoperative period, and in patients with AVP-D who are acutely ill and have desmopressin withheld because they are made nil per os (NPO). Although less common, hypernatremia can develop in patients with AVP-D who also have hypodipsia or adipsia due to certain central nervous system lesions or who have autoantibodies to the subfornical organ [41]. If severe hypernatremia develops rapidly, profound neurological disturbances can occur, called hypernatremic encephalopathy. (See "Etiology and evaluation of hypernatremia in adults", section on 'Adipsic diabetes insipidus'.)
Patients with AVP deficiency often report psychological symptoms such as increased anxiety, social isolation, and a generally decreased quality of life, even if their polyuria and polydipsia are well treated [97]. This psychopathology was suggested to be due to a possible oxytocin-deficient state, which has been reported in one study [98].
Any form of AVP-D can be exacerbated or first become apparent during pregnancy since catabolism of AVP is increased by vasopressinases released from the placenta [99,100]. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)
DIAGNOSIS AND POSTDIAGNOSTIC EVALUATION
Confirming the diagnosis — In normonatremic patients who have symptoms consistent with an arginine vasopressin disorder (eg, polyuria, nocturia, and polydipsia not resulting from uncontrolled diabetes mellitus or another obvious cause), the approach to confirming the diagnosis of AVP-D is as follows (see "Evaluation of patients with polyuria", section on 'When the cause is not obvious'):
●Establish the presence of a water diuresis – Patients with confirmed polyuria (ie, urine output >40 to 50 mL/kg/day, typically assessed with a 24-hour urine collection) may have a solute diuresis or a water diuresis (algorithm 1). In such patients, a urine osmolality <300 mosmol/kg confirms the presence of a water diuresis. A urine osmolality >600 mosmol/kg confirms the presence of a solute diuresis. In patients with an intermediate urine osmolality (ie, between 300 and 600 mosmol/kg), then the total daily solute excretion is calculated (which is equal to the urine osmolality multiplied by the total urine volume on a 24-hour specimen). If the total daily solute excretion is <1000 mosmol, then the patient has a water diuresis. (See "Evaluation of patients with polyuria", section on 'Determining if further testing is necessary'.)
●Establishing the presence of AVP-D – Patients with polyuria and a water diuresis may have AVP-D, arginine vasopressin V2 resistance (AVP-R), or primary polydipsia. These three disorders can be distinguished using plasma copeptin (only if reliable assays are available) (algorithm 2), or with a water restriction test and assessing the response to desmopressin (algorithm 3). These procedures are discussed in detail elsewhere. (See "Evaluation of patients with polyuria", section on 'Water restriction (or hypertonic saline) test'.)
The diagnosis of arginine vasopressin disorders differs in patients who have hypernatremia. (See "Etiology and evaluation of hypernatremia in adults", section on 'Evaluation of hypernatremia' and "Evaluation of patients with polyuria", section on 'Patients with hypernatremia'.)
Postdiagnostic evaluation to determine the etiology — Once the diagnosis of AVP-D has been confirmed, the next step is to determine its cause. Among patients with a physiologic diagnosis of AVP-D, our approach to determining the etiology is as follows:
●AVP-D immediately following neurosurgery or trauma – In patients whose polyuria develops immediately after surgery in the sellar or suprasellar region, severe head trauma, or basilar skull fracture, AVP-D is typically transient. However, as noted above, some patients may develop permanent AVP-D. (See 'Neurosurgery or trauma' above.)
●Initial testing with MRI – Except in patients with transient AVP-D due to neurosurgery or trauma, we perform brain MRI without and with contrast, focusing on the suprasellar region of the hypothalamus, the pituitary stalk, and the anterior and posterior pituitary glands within the sella turcica.
In some patients, MRI will identify the cause of AVP-D, such as a malignancy or infarction. It is important to note that primary tumors of the pituitary gland are slow growing and almost never cause AVP-D; therefore, if such a tumor is diagnosed, alternative etiologies of the AVP-D should be investigated.
●If MRI does not reveal etiology – In most healthy individuals, the AVP and oxytocin that are stored in neurosecretory granules in the pituitary gland can be seen as a "bright spot" on T1-weighted MRI images. This is a high-intensity signal in the posterior part of the sella turcica.
Loss of the pituitary hyperintense spot or bright spot on a T1-weighted MRI image reflects the loss of functional integrity of the neurohypophysis. The intensity of the bright spot correlates with the amount of stored AVP [101], which may diminish or be absent normally in older adults or in dehydrated patients (eg, diabetic ketoacidosis). Severe forms of AVP-R may be associated with an absent bright spot, presumably due to depletion of AVP stores from the posterior pituitary [102].
This bright spot is absent in nearly all patients with AVP-D (except in patients with adipsic AVP-D who produce AVP but do not secrete it in response to osmotic stimuli) or in patients with very-early onset AVP-D or mild forms of partial AVP-D [7]. In addition, patients with AVP-D may have a thickened pituitary stalk (ie, >2.5 mm). The findings of an absent bright spot with or without a thickened pituitary stalk are nonspecific findings and are consistent with autoimmune neurohypophysitis, infiltrative disorders, infectious etiologies, and idiopathic disease.
Patients with nonspecific MRI findings may have obvious, concurrent peripheral manifestations of a disorder that is responsible for the AVP-D. As examples, patients with Langerhans cell histiocytosis often have lytic bone lesions, whereas those with sarcoidosis may have pulmonary manifestations. If a condition that can cause AVP-D (in addition to the patient's peripheral manifestations) is diagnosed, then no further etiologic evaluation of the AVP-D is necessary.
However, if there are no obvious manifestations of an associated condition, then additional investigation should be performed:
•Blood levels of angiotensin converting enzyme (ACE), alpha-fetoprotein (AFP), and human chorionic gonadotropin beta (beta-hCG), to evaluate for sarcoidosis and histiocytosis
•Chest radiograph (or chest computed tomography [CT]), to evaluate for sarcoidosis
•Tuberculin skin test (TST) or interferon-gamma release assay (IGRA) blood test, to evaluate for tuberculosis
•Serum IgG4 level, to evaluate for IgG4-related disease
If the above testing is unhelpful in identifying a diagnosis, then the following tests can be performed:
•Full-body positron emission tomography (PET)/CT, or skeletal survey for patients unable to undergo PET/CT, to evaluate for bony lesions associated with Langerhans cell histiocytosis
•Lumbar puncture with measurement of cerebrospinal fluid ACE, AFP, and beta-hCG, as well as cytology and flow cytometry, to evaluate for leukemia and lymphoma
•Measurement of rabphilin-3A antibodies, which are present in some cases of autoimmune neurohypophysitis
Positive results should be confirmed by biopsy of affected organs (eg, lymph node biopsy, bone biopsy). If all tests are negative, the MRI should be repeated in three to six months and then yearly for five years. Anterior pituitary function should also be assessed yearly (particularly prolactin, since inflammation/infiltration of the pituitary stalk can compress the pituitary portal capillaries and decrease delivery of dopamine to the anterior pituitary lactotrophs). Regression of the pituitary stalk thickening strongly supports a diagnosis of autoimmune neurohypophysitis, whereas progressive stalk thickening is more consistent with an infiltrative lesion requiring a pituitary stalk biopsy for definitive diagnosis. It is important to remember, however, that in autoimmune neurohypophysitis, the stalk thickening typically increases for one to two years after the onset of AVP-D before regressing [35].
The importance of following the MRI serially is that some patients with nonspecific findings initially later develop characteristics suggestive of a germinoma or histiocytosis [103]. In children, progressive thickening of the stalk rather than regression by serial MRIs is strongly suggestive of a germinoma [7].
●Rare patients with a family history suggestive of AVP-D – In patients who have family members with symptoms of an AVP disorder, genetic testing in an accredited laboratory should be performed to evaluate for a known genetic cause.
●No cause identified despite the evaluation presented above – Patients without an identifiable cause despite the above evaluation (including an unrevealing MRI performed annually for five years) are diagnosed as having idiopathic AVP-D. As described, many such patients may have autoimmune neurohypophysitis.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Fluid and electrolyte disorders in adults".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Arginine vasopressin disorders (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Definition – Arginine vasopressin deficiency (AVP-D), previously called central diabetes insipidus, is characterized by decreased release of arginine vasopressin (AVP) (figure 1), also known as antidiuretic hormone (ADH), resulting in variable degrees of polyuria. Damage or dysfunction of any part of the neurohypophysis, if sufficiently severe, can cause AVP-D. (See 'Introduction' above and 'Pathophysiology' above.)
●Epidemiology – AVP-D is a rare disorder. Most cases are acquired; genetic causes account for fewer than 5 percent of cases (table 1). (See 'Epidemiology' above.)
●Etiology – Acquired AVP-D accounts for the majority of cases (table 1). The most common acquired causes of AVP-D are neurosurgery, head trauma, autoimmune neurohypophysitis, primary or secondary tumors, and infiltrative diseases (such as Langerhans cell histiocytosis and sarcoidosis). (See 'Acquired causes' above.)
Several familial and congenital diseases are associated with AVP-D. These include familial AVP-D, Wolfram syndrome, proprotein convertase subtilisin/kexin type 1 (PCSK1) gene deficiency, and congenital diseases such as congenital hypopituitarism and septo-optic dysplasia (SOD). (See 'Genetic or congenital causes' above.)
●Clinical manifestations – Patients with untreated AVP-D typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia. Depending upon the specific cause of the AVP-D, patients may also have neurologic symptoms related to the underlying disorder, such as diplopia and headache. The serum sodium concentration in untreated AVP-D is often in the high normal range; moderate to severe hypernatremia can develop when thirst is impaired or cannot be expressed or if there is no access to water. (See 'Clinical manifestations' above.)
●Confirming the diagnosis – In normonatremic patients who have symptoms consistent with an arginine vasopressin disorder, the diagnosis is confirmed by, initially, establishing the presence of a water diuresis and (algorithm 1), subsequently, distinguishing AVP-D from arginine vasopressin V2 resistance (AVP-R, formerly called nephrogenic diabetes insipidus) and primary polydipsia (algorithm 2 and algorithm 3). (See 'Confirming the diagnosis' above.)
●Etiologic evaluation – Once the diagnosis of AVP-D has been confirmed, the next step is to determine its cause. Among patients with a physiologic diagnosis of AVP-D, our approach to determining the etiology is as follows (see 'Postdiagnostic evaluation to determine the etiology' above):
•In patients whose polyuria develops immediately after surgery in the sellar or suprasellar region, severe head trauma, or basilar skull fracture, no further evaluation is needed.
•In patients whose symptoms are unrelated to neurosurgery or head trauma, we perform brain MRI without and with contrast, focusing on the suprasellar region of the hypothalamus, the pituitary stalk, and the anterior and posterior pituitary glands within the sella turcica.
•Patients with nonspecific MRI findings may have obvious, concurrent manifestations of a disorder that is responsible for the AVP-D (eg, Langerhans cell histiocytosis, sarcoidosis). If a condition that can cause AVP-D (in addition to the patient's other manifestations) is diagnosed, then no further etiologic evaluation of the AVP-D is necessary.
•If there are no obvious manifestations of an associated condition, then additional investigation should be performed: blood levels of angiotensin converting enzyme (ACE), alpha-fetoprotein (AFP), and human chorionic gonadotropin beta (beta-hCG); chest radiograph (or chest CT); tuberculin skin test (TST) or interferon-gamma release assay (IGRA) blood test; and serum IgG4 level. If these tests are unrevealing, then additional tests may also be performed, including full-body imaging, lumbar puncture, and measurement of rabphilin-3A antibodies.
•In patients who have family members with symptoms of an AVP disorder, genetic testing in an accredited laboratory should be performed to evaluate for a known genetic cause.
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