Approach

Arginine vasopressin deficiency (AVP-D; previously known as central diabetes insipidus) and arginine vasopressin resistance (AVP-R; previously known as nephrogenic diabetes insipidus) are disorders of water homeostasis characterised by the excretion of abnormally large volumes of hypotonic urine.[1]​​[3]​​[5]​ The approach to diagnosis requires confirming significant polyuria (as opposed to urinary frequency with normal total daily urine output), eliminating primary polydipsia (excess intake of water) as the underlying cause of polyuria, and then establishing whether the patient has AVP-D (defective synthesis or release of AVP from the hypothalamo-pituitary axis) or AVP-R (renal insensitivity or resistance to AVP).[1]​​[3]​​[5]

Once AVP-D or AVP-R is confirmed, the clinical review and investigations can be directed to identify the underlying cause.

History

Congenital malformations and inherited causes of AVP-D and AVP-R usually present in the first year of life with faltering growth, polyuria, and vomiting.​[40][53]

Patients with neurosurgical conditions (e.g., traumatic brain injury, subarachnoid haemorrhage, trans-sphenoidal surgery) may develop AVP-D (usually transient) within the first few days of the event.[3]​​

Patients with non-traumatic AVP-D usually present with symptoms developing over weeks or months. The same natural history is generally seen in AVP-R, although those patients with inherited forms present with long-standing symptoms from an early age.

Presenting symptoms

  • Patients typically present with polyuria, polydipsia, and thirst of variable severity and duration. A 24-hour urine output of >3 litres (or >50 mL/kg/day) requires investigation.[3]​​​

  • Polyuria in AVP-D and AVP-R usually requires voiding every hour throughout the day and night, and significant nocturia is a common presenting feature.[10] Children may have bedwetting.[25]

  • Severe volume depletion is uncommon, as the increased thirst-stimulated drinking is usually strong enough to balance the increased renal water loss. If thirst is decreased (e.g., due to primary pathology [adipsia], reduced consciousness) or access to free water is limited (e.g., non-availability, disability, intercurrent illness), the patient may become dehydrated and develop hypernatraemia.​[54]

Medical history to assess for conditions associated with AVP-D or AVP-R

  • A history of traumatic brain injury or pituitary disease, including any recent or past neurosurgery, is important to consider. With the exception of craniopharyngioma, germinoma, granulomatous disease, or metastases from distant tumours, it is uncommon for AVP-D to present preoperatively in patients with pituitary disease.​[25]​ Therefore, the presence of AVP-D at diagnosis raises suspicion for one of these conditions and makes adenomatous pituitary disease an unlikely diagnosis.[1]

  • AVP-D may develop as a complication of subarachnoid haemorrhage, meningitis, or encephalitis.

  • Systemic conditions that involve the pituitary stalk can cause AVP-D. These include Langerhans' cell histiocytosis, sarcoidosis, and tuberculosis.[1]​​[17][20]

  • A history of other autoimmune diseases, such as Hashimoto's thyroiditis, diabetes mellitus type 1, or systemic lupus erythematosus, should raise suspicion of an autoimmune process involving the hypothalamo-pituitary axis producing AVP-D.[3][28]

  • Hypercalcaemia, hypokalaemia, chronic kidney disease, renal sarcoidosis, and renal amyloidosis are recognised causes of AVP-R.[5][10]

Family history

  • A family history may help identify patients with genetic causes of either AVP-D or AVP-R.

  • AVP-D may occur in patients with AVP-neurophysin gene mutations, inherited in an autosomal dominant pattern. It may also be a component of Wolfram syndrome (also called DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness] syndrome), an autosomal recessive, progressive neurodegenerative disorder.[39][41]​​​

  • AVP-R may occur in patients with mutations in the AVP receptor pathway.[5][10]​ Most (90%) of inherited cases are AVPR2 mutations, which have an X-linked pattern of inheritance, and, consequently, the majority of patients are male.[10] Mutations on the AQP2 gene (10% of cases) typically have autosomal recessive inheritance, although a few mutations cause autosomal dominant disease.[10]

Drug history

  • AVP-R occurs in up to 40% of patients receiving long-term lithium therapy, though some reports suggest the incidence may be as high as 85%.[9][10]​​ Other drugs associated with AVP-R include demeclocycline, cisplatin, colchicine, gentamicin, rifampicin, and sevoflurane.[5][44]

Physical examination

Severe volume depletion or hypernatraemia is uncommon, as the thirst response is usually strong enough to offset this. However, in patients where free access to water is impaired (e.g., in children and older patients, cognitive or physical impairment, adipsia [loss of thirst perception due to damage to anterior hypothalamic osmoreceptors, often caused by the same lesion responsible for AVP deficiency]), examination may show:

  • Signs of volume depletion: dry mucous membranes, reduced skin turgor, tachycardia, and postural hypotension.

  • Evidence of hypernatraemia: symptoms and signs are non-specific. Central nervous system (CNS) manifestations include irritability, restlessness, lethargy, muscle twitching, spasticity, and hyper-reflexia. If hypernatraemia is severe, delirium, seizures, and coma may be present.[55]

CNS examination

  • Visual field defects may indicate a previous or contemporary pituitary mass.[3]​​

  • Focal motor deficits may be present due to previous intracranial pathology (e.g., tumour, subarachnoid haemorrhage, meningitis, or encephalitis).

  • Visual failure with optic atrophy and sensorineural deafness may suggest Wolfram syndrome.[41]

Skin lesions

  • Cutaneous lesions (e.g., skin rash or erythema nodosum) may suggest systemic Langerhans' cell histiocytosis or sarcoidosis.

Anterior pituitary dysfunction associated with AVP-D

  • In cases with sellar or parasellar masses leading to AVP-D, evidence of hypopituitarism is often present.

  • In adults, clinical manifestations of hypopituitarism include erectile dysfunction, menstrual disturbances, and fatigue.[56]​ In children, growth and development are affected.[24][25]

  • AVP-D may be masked by co-existing adrenocorticotrophic hormone (ACTH) deficiency, which leads to secondary adrenal insufficiency and reduced cortisol production. Cortisol plays a critical role in free water clearance by suppressing AVP secretion and promoting renal water excretion. In the absence of adequate cortisol, water retention may obscure the typical polyuria seen in AVP-D. As a result, AVP-D may only become clinically apparent after glucocorticoid replacement restores normal cortisol levels and unmasks the underlying AVP deficiency.[3]​​

  • For further information on hypopituitarism, see Hypopituitarism.

Initial investigations

Initial laboratory tests in all patients with suspected AVP-D or AVP-R are serum electrolytes (including sodium, potassium and calcium), glucose (to exclude diabetes mellitus as a cause of polyuria), measurement of urine and serum osmolality (or calculated), and confirmation of polyuria with 24-hour urine collection.

It should be recognised that diabetes mellitus can co-exist with AVP-D or AVP-R.

The predicted serum osmolality can be calculated on the basis of the serum sodium, potassium, glucose, and blood urea nitrogen. [ Osmolality Estimator (serum) Opens in new window ]

The clinical definition of polyuria varies across the literature. It has been defined as urine output exceeding 50 mL/kg of body weight per day in adults, or more arbitrarily as >3 L/day.[3] These differing thresholds highlight the absence of a unified consensus from endocrine societies on the diagnostic criteria for AVP-D and AVP-R. In practice, if an adult has a daily urine volume of less than 2.5 L, further endocrine investigations are typically unnecessary, though urological referral may be appropriate.[3]

A reduced urine osmolality <300 mmol/kg (<300 mOsm/kg) in conjunction with high serum osmolality >290 mmol/kg (>290 mOsm/kg) or elevated serum sodium strongly suggests AVP-D or AVP-R. An ability to concentrate urine >600 mmol/kg (>600 mOsmol/kg) makes AVP-D or AVP-R unlikely.

Patients with AVP-D or AVP-R often have plasma sodium levels at the upper end of the normal range. In contrast, those with primary polydipsia typically exhibit low or low-normal plasma sodium and low plasma osmolality due to excessive fluid intake, which suppresses AVP secretion and leads to polyuria. Thus, patients with hyponatraemia in the context of hypotonic polyuria are likely to have primary polydipsia rather than AVP-D or AVP-R.

Water deprivation and AVP (desmopressin) stimulation test

The water deprivation test (WDT) has historically been the standard method of confirming a diagnosis of AVP-D and AVP-R by confirming inability to concentrate urine appropriately during supervised dehydration. A second component of this test, involving AVP stimulation (with the synthetic AVP analogue desmopressin [also known as DDAVP]), is used only in those patients with confirmed inability to concentrate urine appropriately on dehydration, to distinguish between AVP-D and AVP-R.

Several points should be considered prior to embarking on the WDT and AVP stimulation tests.

  • WDT should only be performed in a unit that has expertise in performing and interpreting the test.

  • If serum sodium is elevated while the urine osmolality is <300 mmol/kg (<300 mOsm/kg), the WDT is unnecessary and should not be performed. In this setting, patients should be treated with desmopressin and the response (urine output, serum sodium, urine osmolality) noted.

  • The test should not be performed in patients with renal insufficiency, uncontrolled diabetes mellitus, or if there is co-existing uncorrected adrenal or thyroid hormone deficiency.

  • Patients are deprived of all fluids for 8 hours or until a 3% loss of their body weight is reached.

  • Careful monitoring of water balance is essential. The patient should be observed for the entirety of the test.

  • Serum osmolality, urine volume, and urine osmolality is measured hourly. The test can only be interpreted in the setting of achieving a raised plasma osmolality.

  • Failure to concentrate urine appropriately (thus indicating AVP-D or AVP-R) is confirmed by a final urine osmolality <300 mmol/kg (<300 mOsm/kg) with corresponding plasma osmolality >290 mmol/kg (>290 mOsm/kg). This threshold is important in determining progression to the second phase of the test: AVP-analogue (desmopressin) stimulation to differentiate between AVP-D and AVP-R.

  • In this second phase, patients are given desmopressin subcutaneously. Serum and urine osmolality, and urine volume, are measured hourly over the next 4 hours.

  • In patients with AVP-D, the kidneys respond to desmopressin with a reduction in urine output and an increase in urine osmolality to >750 mmol/kg (>750 mOsm/kg).

  • In patients with AVP-R, there is a lack of response to desmopressin, with no or little reduction in urine output and little or no increase in urine osmolality.

  • In the assessment of pituitary function after neurosurgery, the second step - administration of desmopressin - is unnecessary, as the aim of water deprivation is simply to establish the presence or absence of AVP-D.[3]

The WDT has several limitations: patient acceptability is low (the test is unpleasant for patients with primary polydipsia); the protocol is resource-intense (requiring a day in hospital, with careful supervision by experienced staff to prevent surreptitious drinking in primary polydipsia); and sensitivity and specificity are limited by the high prevalence of partial concentrating defects, meaning many test results are indeterminate. Chronic polyuria due to longstanding primary polydipsia can also blunt maximal renal concentrating capacity by reducing the intrarenal medullary concentration gradient.[3]​ The diagnostic accuracy for WDT is around 70% to 75% for all polyuric states, with similar accuracy in differentiating partial AVP-D from primary polydipsia.[57][58] Furthermore, the WDT can be hazardous in patients with complete AVP-D, as they are at risk of developing hypernatraemic dehydration.​[3]​ Patients should be well-hydrated before the test, and if adipsia is suspected, plasma osmolality should be urgently measured to rule out pre-existing dehydration.[3]​ Baseline body weight should be recorded and monitored every 2 hours; a loss of 5% or more from baseline indicates significant dehydration.[3]​ In such cases, serum electrolytes should be urgently checked, and the test should be stopped immediately to initiate rehydration.[3]

Hypertonic saline stimulation testing and measurement of copeptin

The WDT is an indirect test of the AVP axis, using renal concentrating ability as a functional surrogate for measuring AVP. A more desirable and modern approach to the biochemical confirmation of relative or absolute lack of AVP is the direct measurement of AVP during standardised osmolar stress.[3] However, direct measurement of AVP is limited by its short circulating half-life and the restricted availability of reliable immunoassays.

​An alternative approach is to use copeptin as a surrogate for AVP.[3]​ Copeptin is the c-terminal fragment of the larger AVP-precursor synthesised within the magnocellular neurons of the supraoptic and paraventricular nuclei. It is cleaved from the precursor as one of the final steps in post-translational processing within secretory granules at the nerve terminals in the posterior pituitary. Copeptin is released in equimolar amounts to AVP.[3]​ Importantly, it is much more stable and much easier to develop as a sustainable direct measure of the AVP axis.[3]

  • In AVP-R, impaired kidney response to AVP leads to compensatory high AVP (and copeptin) levels.

  • Conversely, baseline copeptin remains low in AVP-D (due to deficient AVP production), as well as in primary polydipsia (because excessive water intake suppresses AVP secretion by lowering osmolar stimulus).

  • A baseline (without water deprivation or hypertonic saline-stimulation) copeptin level >21.4 pmol/L reliably differentiates AVP-R from both primary polydipsia and AVP-D, with 100% sensitivity and specificity.[59]

  • During hyperosmolar stimulation, in which a 3% sodium chloride infusion is used to artificially raise plasma osmolality, a copeptin level greater than 4.9 pmol/L can differentiate primary polydipsia from AVP-D with 96% diagnostic accuracy.[58]​ Patients with AVP-D fail to mount an adequate AVP/copeptin response, so copeptin remains below the threshold.

Due to potential side effects, such as intense thirst, nausea, and headache, the hypertonic saline stimulation test should be performed under close supervision in a specialist setting.[60]​ Arginine-stimulated copeptin measurement may be a safer alternative but has lower diagnostic accuracy (74% vs. 96%).[60]

Subsequent investigations to establish the cause

Cranial imaging (pituitary magnetic resonance imaging [MRI])

  • Should be ordered in all patients with AVP-D. MRI is the imaging modality of choice. Ordinarily, the posterior pituitary typically shows up as a bright spot on T1-weighted sequences. The intensity of this T1 'bright spot' reflects the extent of stored AVP within neurosecretory granules. Loss of the bright spot is the classical MRI finding in AVP-D, indicating depletion or absence of stored AVP.[3]​ While this finding has high sensitivity, its specificity is limited.[3]​ The bright spot can also be absent in healthy individuals, particularly in older adults, due to an age-related decline in AVP storage, and in a small number of younger people.[3]​ Additionally, up to 40% of patients with primary polydipsia may lack the bright spot, possibly due to suppressed AVP synthesis from chronic hypo-osmolality.[3]​ Conversely, modern imaging studies show that up to 20% of patients with confirmed complete AVP-D and 40% with partial AVP-D may still retain the bright spot, likely due to residual AVP or oxytocin granules.[3]​ Thus, while the absence of the bright spot is a useful diagnostic clue, it should always be interpreted alongside clinical and biochemical findings.[3]

  • Evidence of pituitary enlargement, including increased pituitary stalk thickness or a pituitary mass, may suggest the underlying pathology of AVP-D (e.g., pituitary stalk thickening may suggest an autoimmune cause, while a pituitary mass should raise the possibility of craniopharyngioma, granulomatous disease, or other inflammatory conditions).[3][4][24][61]

    • Craniopharyngiomas are typically suprasellar and have a heterogeneous appearance on MRI; they may also exhibit calcification, best seen on supplementary computed tomography (CT) imaging.[3]​ In contrast, Rathke’s cleft cysts (an important differential diagnosis) are usually confined to the sella, predominantly cystic, and rarely calcify or enhance.[3]​ The presence of both solid and cystic components, particularly with enhancement of the solid portion and cyst wall, is more suggestive of craniopharyngioma.[3]

    • Germinomas may involve the posterior pituitary, but more commonly affect the infundibulum or suprasellar region, appearing iso- or hyperintense on both T1- and T2-weighted MRI sequences.[3]​ Importantly, early MRI may appear normal, particularly in the initial stages.[3]

    • Pituitary gliomas, a rare cause of AVP-D, manifest on MRI as hypointense on T1 weighted images and markedly hyperintense on T2 weighted images.[3]

    • Pituitary stalk metastases, most commonly from breast or bone, may be visible on MRI. Patients usually have a known history of malignancy elsewhere.[3]

  • In patients with strong clinical suspicion of tumour, tuberculosis, or sarcoid, further cross-sectional imaging (e.g., chest or abdominal CT) should be ordered.[3]

  • Repeat imaging is recommended at 6 months and at 12 to 18 months in those with normal initial imaging, as pituitary lesions may not manifest on initial scans.

Genetic testing

  • AVP-D: a family history suggesting familial AVP-D should prompt AVP-neurophysin gene studies. These studies can be used predictively within a kindred with autosomal dominant familial AVP-D.[39]​ Wider features of Wolfram syndrome should prompt consideration of WFSI gene studies.[41]

  • AVP-R: this condition may occur in patients with loss-of-function mutations in the AVP signalling pathway.[5][10]​ The most common mutation is a loss-of-function mutation in the AVPR2 receptor, inherited in an X-linked recessive pattern. AVP-R can also be caused by loss-of-function mutations in the aquaporin-2 water channel genes.[39]

Tumour markers for intracranial germinoma

  • Germinoma should be suspected in children and adolescents (peak age of incidence is 10-24 years) presenting with AVP-D and pituitary stalk thickening.[4][18]

  • In this population, serum and cerebrospinal fluid alpha-fetoprotein and beta-human chorionic gonadotrophin may serve as markers for germ cell tumours and, in some cases, may herald the diagnosis of germinoma prior to the appearance of MRI changes. However, because they lack sensitivity and may be negative in pure germinomas, all patients with AVP-D and pituitary stalk thickening require regular neuroimaging to monitor for disease progression or emergence, regardless of tumour marker results.[3]

Anterior pituitary function testing for associated hypopituitarism

  • AVP-D is commonly found in the context of anterior hypopituitarism, and pituitary function testing should be considered in all those presenting with AVP-D.[54] Anterior pituitary deficits are most likely in cases with a structural cause for AVP-D.[56]​​

  • Assessment includes measurement of pituitary hormones (growth hormone, prolactin, adrenocorticotrophic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, and luteinising hormone), and the hormones from their target organs (insulin-like growth factor 1, cortisol, free thyroxine, total and free testosterone, estradiol).

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