INTRODUCTION — Central diabetes insipidus (CDI) is characterized by decreased release of antidiuretic hormone (ADH; also called arginine vasopressin or AVP), resulting in a variable degree of polyuria. Lack of ADH can be caused by disorders that act at one or more of the sites involved in ADH secretion: the hypothalamic osmoreceptors; the supraoptic or paraventricular nuclei; or the superior portion of the supraopticohypophyseal tract [1]. By contrast, damage to the tract below the median eminence or to the posterior pituitary generally causes only transient polyuria, because ADH produced in the hypothalamus can still be secreted into the systemic circulation via the portal capillaries in the median eminence [1]. (See "Hypothalamic-pituitary axis".)
The clinical manifestations and causes of CDI will be reviewed here. The treatment of CDI, the clinical manifestations and causes of nephrogenic diabetes insipidus (DI), and the diagnostic approach to the polyuric patient are discussed separately:
●(See "Treatment of central diabetes insipidus (vasopressin deficiency)".)
●(See "Clinical manifestations and causes of nephrogenic diabetes insipidus".)
●(See "Evaluation of patients with polyuria".)
CLINICAL MANIFESTATIONS — Patients with untreated central diabetes insipidus (CDI) typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia. They may also have neurologic symptoms related to the underlying neurologic disease.
The serum sodium concentration in untreated CDI is often in the high normal range, which is required to provide the ongoing stimulation of thirst to replace the urinary water losses [2]. Moderate to severe hypernatremia can develop when thirst is impaired or cannot be expressed. This can occur in patients with central nervous system lesions who also have hypodipsia or adipsia, in adipsic young patients who have autoantibodies to the subfornical organ [3], in infants and young children who cannot independently access free water, and in the postoperative period in patients with unrecognized diabetes insipidus (DI). (See "Etiology and evaluation of hypernatremia in adults", section on 'Adipsic diabetes insipidus'.)
Patients with CDI may develop decreased bone mineral density at the lumbar spine and femoral neck, even in those treated with desmopressin (dDAVP) [4]. It is unclear how the deficiency of ADH results in bone loss, particularly since treatment fails to prevent bone disease. However, since ADH acts upon both V1 and V2 receptors and desmopressin principally upon V2 receptors, one possible mechanism is that activation of V1 receptors stimulates bone formation.
CAUSES — The most common causes of central diabetes insipidus (CDI), accounting for the vast majority of cases, are idiopathic diabetes insipidus (DI) [1,5,6], primary or secondary tumors or infiltrative diseases (such as Langerhans cell histiocytosis) [7], neurosurgery, and trauma. In a report of 79 children and young adults, for example, CDI was idiopathic in 52 percent and resulted from a tumor or infiltrative disease in 38 percent [6]. In another cohort of 147 children followed from 2000 to 2013 in a single North American center, the most common single diagnosis was craniopharyngioma (25.2 percent) [8].
Cranial magnetic resonance imaging (MRI) to identify hyperintensities in the posterior pituitary or thickening of the pituitary stalk can help determine the cause of CDI [9-11].
Any form of CDI can be exacerbated or first become apparent during pregnancy, since catabolism of antidiuretic hormone (ADH; also called arginine vasopressin or AVP) is increased by vasopressinases released from the placenta [12,13]. (See "Maternal adaptations to pregnancy: Renal and urinary tract physiology".)
Idiopathic CDI — Approximately 30 to 50 percent of cases of CDI are idiopathic, being 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, patients [14-17]. 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 CDI [15]. Among almost 900 such patients, 9 found to be Ab-positive and 139 Ab-negative controls were prospectively followed. At four years, none of the controls developed CDI. By comparison, four of the nine Ab-positive patients had partial CDI at study entry and, among the remaining five patients, three developed partial DI and one developed complete CDI.
This autoimmune process is characterized by lymphocytic inflammation of the pituitary stalk and posterior pituitary that resolves after destruction of the target neurons. MRI early in the course often reveals thickening or enlargement of these structures.
The incidence of such antibodies in those with CDI, their association with other autoimmune diseases, and their correlation with radiologic features was evaluated in a study of 150 patients with CDI that was performed by the same Italian group [16]. 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 vasopressin cells were found in approximately one-third of the patients with idiopathic disease and approximately one-quarter of patients with nonidiopathic disease. Antibody positivity was independently associated with age less than 30 years at disease onset in those with idiopathic disease, a history of autoimmune disease, or pituitary stalk thickening. Autoimmune CDI was highly probable in young patients with a history of autoimmune disease and pituitary stalk thickening.
The autoantigens involved in idiopathic CDI are not fully elucidated. However, autoantibodies to rabphilin-3A, a regulator of secretory vesicle trafficking, may be found in a large majority of patients with lymphocytic infundibuloneurohypophysitis (LINH) [18]. LINH accounts for a substantial subset of autoimmune CDI and is characterized by lymphocytic inflammation of the posterior pituitary and infundibular stalk (damage to the stalk is what produces CDI) [19].
Other autoimmune mechanisms for CDI include immunoglobulin (Ig) G4-related systemic syndrome, which may be successfully treated with glucocorticoids [20-22], and granulomatosis with polyangiitis (GPA), a systemic disease characterized by pauci-immune, necrotizing, small-vessel vasculitis, often associated with positive antineutrophil cytoplasmic antibodies (ANCA) [23]. In addition, diabetes insipidus may occur in patients with autoimmune polyglandular syndrome type I, which results from a mutation of the autoimmune regulator gene (AIRE) [24]. (See "Pathogenesis and clinical manifestations of IgG4-related disease" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)
Thickening of the pituitary stalk is a nonspecific finding, since some patients with this finding later develop a germinoma or histiocytosis [25]. In children, progressive thickening of the stalk as determined by serial MRIs is strongly suggestive of a germinoma [6].
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 CDI [6,26]. However, some patients who develop an anterior pituitary endocrinopathy years after the diagnosis of CDI may have a pituitary or suprasellar tumor or other generalized lesion, suggesting that the initial abnormality was due to an occult pathologic process [27-29]. As an example, in one study of 16 patients first diagnosed with idiopathic CDI, 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 [27]. Thus, patients diagnosed with idiopathic CDI should generally undergo regular endocrine follow-up. (See "Diagnostic testing for hypopituitarism".)
Familial and congenital disease — A number of familial and congenital diseases have been associated with CDI. These include familial CDI, Wolfram syndrome, proprotein convertase subtilisin/kexin type 1 (PCSK1) gene deficiency, and congenital diseases such as congenital hypopituitarism and septo-optic dysplasia.
Familial CDI — Familial CDI, also called familial neurohypophyseal DI, or FNDI (MIM 125700), is usually an autosomal dominant disease caused by mutations in the gene encoding antidiuretic hormone (ADH; also called arginine vasopressin or AVP) [30]. ADH and its corresponding carrier, neurophysin II, are synthesized as a composite precursor by the magnocellular neurons of the supraoptic and paraventricular nuclei of the hypothalamus [31].
The mechanism underlying the "dominant-negative" effect of autosomal familial CDI mutations involves the retention of the mutant ADH prohormone in the endoplasmic reticulum (ER) of magnocellular neurons [32]. Mutant ADH, and functional ADH protein produced from the nonaffected allele, form high-molecular-weight complexes that are destined for ubiquitylation and proteasomal degradation by the ER quality-control pathway ER-associated degradation (ERAD) [33]. This model helps explain results obtained in some mouse models of DI with human proAVP mutations, in which ADH-producing neuronal cell death was not observed at disease onset and was therefore not thought to have a role in disease initiation [34].
This autosomal dominant form of CDI contrasts with congenital ADH deficiency that has been described in three families with autosomal recessive CDI. Two families bear a missense variation affecting the seventh amino acid of the ADH nonapeptide (p.Pro26Leu) [35,36], 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 gene [37]. Affected members have early polyuria and hypernatremia, in contrast to the autosomal dominant disease mentioned above. The existence of this autosomal recessive, early onset CDI is important because it must be considered, along with congenital nephrogenic DI, in the differential diagnosis of congenital polyuria and dehydration, and therapy for these disorders differ.
Wolfram syndrome — The Wolfram or DIDMOAD (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) syndrome is characterized by CDI, diabetes mellitus, optic atrophy, and deafness, with cognitive and psychiatric issues that may appear later in life [38]; 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 [39]. 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 [40] and brain supraoptic paraventricular nuclei [41]. DI in this disorder is due to loss of vasopressin-secreting neurons in the supraoptic nucleus and impaired processing of vasopressin precursors [42].
Variations in WFS1 also predispose to type 2 diabetes mellitus [43]. 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 vasopressin deficiency [44]. (See "Classification of diabetes mellitus and genetic diabetic syndromes", section on 'Wolfram syndrome'.)
Proprotein convertase subtilisin/kexin-type 1 (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 [45]. PC1/3 is involved in the processing of numerous digestive and hypothalamic prohormones, including ADH. More than 25 cases of PC1/3 deficiency have been reported in the literature; 30 percent were of Turkish origin [46,47]. All individuals had early and severe malabsorptive diarrhea, and approximately 80 percent had polyuria-polydipsia syndrome (before 5 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 [46].
Congenital hypopituitarism — CDI has been described in patients with congenital hypopituitarism with or without ectopia of the posterior pituitary lobe [48-50]. The defects in posterior pituitary function in these disorders include symptomatic CDI, nocturia, reduced ADH release after osmotic challenge, and hypodipsia or polydipsia. These findings may be associated with isolated growth hormone deficiency or multiple anterior pituitary hormone deficiencies.
Septo-optic dysplasia — CDI can be seen in a number of congenital cerebral midline abnormalities. As an example, septo-optic dysplasia (SOD) has been associated with defects in both anterior and posterior pituitary function [51,52]. 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 [53]. Affected patients may have abnormal thirst as well as a defect in ADH release [52,54]. As a result, we recommend monitoring of the serum sodium in these patients once per week for one month, and then if stable, once every six months.
Neurosurgery or trauma — CDI can be induced by neurosurgery (usually transsphenoidal) or trauma to the hypothalamus and posterior pituitary [55-59]. The incidence of CDI 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 very large tumors.
A much lower rate of postoperative CDI has been reported with minimally invasive endoscopic pituitary surgery (2.7 percent permanent and 13.6 percent transient) [60]. A serum sodium higher than 145 mEq/L within the first five postoperative days had a high predictive value for permanent DI development. By contrast, patients with a serum sodium less than 145 mEq/L in the first five postoperative days will rarely, if ever, develop permanent DI, thereby validating short postoperative inpatient stays with minimal risk of readmission for DI management.
Craniopharyngioma has been associated with CDI both before surgery and particularly after surgery [57,61]. A somewhat different response has been detected after transfrontal surgery for a craniopharyngioma. In this setting, the polyuria appears to result in at least some patients from the release of an ADH precursor from the hypothalamus that competes for but does not activate ADH V2 receptors [59]. These patients initially have high serum immunoreactive ADH concentrations, but their ADH has little or no biological activity and they have diminished response to exogenous hormone replacement. Thus, they behave as if they have nephrogenic DI (NDI), although the polyuria is typically transient.
Severe damage to the hypothalamus or tract by neurosurgery or trauma often results in a typical triphasic response [1,57]. There is an initial polyuric phase, beginning within 24 hours and lasting 4 to 5 days; this phase reflects inhibition of ADH release due to hypothalamic dysfunction [55]. This is followed, on days 6 to 11, by an antidiuretic phase in which stored hormone is slowly released from the degenerating posterior pituitary. During this stage, excessive water intake can lead to hyponatremia because of a transient syndrome of inappropriate ADH secretion [62]. Permanent DI may then ensue after the posterior pituitary stores are depleted.
Most cases are not permanent [63]. As an example, patients with less severe hypothalamic or tract injury often have transient CDI that begins 24 to 48 hours after surgery and may then resolve over the first week. Furthermore, not all patients progress through all three phases. Some patients develop transient hyponatremia, with or without preceding polyuria, and then recover. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)".)
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 these different responses [64]. Among these patients, 30 percent had microadenomas and 70 percent macroadenomas. The key findings were:
●31 percent had immediate postoperative polyuria, 17 percent had polyuria on day three, and 6 percent on day seven. Of these patients, 24 percent received one or more doses of ADH. After three months, only 0.9 percent were still receiving ADH or had polyuria.
●3.4 percent of patients had transient polyuria and then transient hyponatremia.
●1.1 percent had the 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.
Despite the relatively high frequency of CDI in patients undergoing neurosurgery, most cases of polyuria in this setting are not due to CDI [55]. More common causes are excretion of excess fluid administered during surgery [65] and/or an osmotic diuresis induced by mannitol or glucocorticoids (which cause hyperglycemia and glucosuria) given in an attempt to reduce cerebral edema. These conditions can be differentiated from CDI by measuring the urine osmolality and the response to water restriction and the administration of ADH. (See "Evaluation of patients with polyuria".)
CDI after neurosurgery rarely occurs in combination with cerebral salt-wasting. Depending upon the balance of the ensuing water and solute (NaCl) diuresis, hyponatremia, normonatremia, or hypernatremia may be present [66]. (See "Pathophysiology and etiology of the syndrome of inappropriate antidiuretic hormone secretion (SIADH)", section on 'Cerebral salt wasting'.)
Cancer — Primary or secondary (most often due to lung cancer, leukemia, or lymphoma) tumors in the brain can involve the hypothalamic-pituitary region and lead to CDI [5]. CDI may also be observed in myelodysplastic syndrome [67]. In some patients with metastatic disease, polyuria is the presenting symptom [5].
Hypoxic encephalopathy — Hypoxic encephalopathy or severe ischemia (as with cardiopulmonary arrest or shock) can lead to diminished ADH release [1,68]. The severity of this defect varies, ranging from mild and asymptomatic to marked polyuria. As an example, overt CDI is unusual in patients with Sheehan's syndrome (postpartum hypopituitarism) even though ADH secretion is often subnormal [69]. The appearance of DI in these patients is consistent with the occasional pathologic findings of scarring and atrophy in the supraoptic nuclei and posterior pituitary gland [70]. (See "Causes of hypopituitarism".)
Infiltrative disorders — Patients with Langerhans cell histiocytosis (also called histiocytosis X and eosinophilic granuloma) are at particularly high risk for CDI due to hypothalamic-pituitary disease [7,71]. Up to 40 percent of patients become polyuric within the first four years, particularly if there is multisystem involvement and proptosis. (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 NDI (induced by hypercalcemia) or primary polydipsia [72]. Additional infiltrative disorders that rarely cause CDI include granulomatosis with polyangiitis [73,74] and autoimmune lymphocytic hypophysitis [14,75-77]; the latter disorder may spontaneously improve. (See "Causes of hypopituitarism", section on 'Hypophysitis'.)
Post-supraventricular tachycardia — Transient polyuria is occasionally seen after correction of a supraventricular tachycardia [78,79]. Both a water diuresis and a natriuresis may be seen, due respectively due to decreased secretion of ADH 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 — ADH release is often subnormal or erratic in patients with anorexia nervosa, presumably due to the cerebral dysfunction [80]. This defect is relatively mild in most cases and polyuria, when present, is often due mostly to a primary increase in thirst.
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: Diabetes insipidus (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Pathogenesis – Central diabetes insipidus (CDI) is characterized by decreased release of antidiuretic hormone (ADH), resulting in a variable degree of polyuria. Lack of ADH can be caused by disorders that act at one or more of the sites involved in ADH secretion: the hypothalamic osmoreceptors, the supraoptic or paraventricular nuclei, or the superior portion of the supraopticohypophyseal tract. (See 'Introduction' above.)
●Clinical manifestations – Patients with untreated CDI typically present with polyuria, nocturia, and, due to the initial elevation in serum sodium and osmolality, polydipsia. They may also have neurologic symptoms related to the underlying neurologic disease. (See 'Clinical manifestations' above.)
●Etiology – The causes of CDI include idiopathic disease, familial and congenital disorders, neurosurgery or trauma, primary or secondary cancers, hypoxic encephalopathy, infiltrative disorders, post-supraventricular tachycardia, and anorexia nervosa. The vast majority of cases are due to idiopathic CDI or result from primary or secondary tumors, or infiltrative diseases (such as Langerhans cell histiocytosis). (See 'Causes' above.)
