Approach
AVP deficiency (AVP-D; previously known as central diabetes insipidus) and AVP resistance (AVP-R; previously known as nephrogenic diabetes insipidus) are disorders of water homeostasis characterized 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.[38][52]
Patients with neurosurgical conditions (e.g., traumatic brain injury, subarachnoid hemorrhage, transsphenoidal surgery) may develop AVP-D (usually transient) within the first few days of the event.[3]
Patients with nontraumatic 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 longstanding symptoms from an early age.
Presenting symptoms
Patients typically present with polyuria, polydipsia, and thirst of variable severity and duration. The extent of polyuria ranges from 3 liters to >20 liters per day. A 24-hour urine output of >3 liters (50 mL/kg/day) require investigation.[53]
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.[26]
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., nonavailability, disability, intercurrent illness), the patient may become dehydrated and develop hypernatremia.[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 previous neurosurgery, is key. With the exception of craniopharyngioma, germinoma, granulomatous disease, or metastases from distant tumors it is uncommon AVP-D to present preoperatively in patients with pituitary disease.[26] Therefore, if AVP-D is present at diagnosis, it is suspicious for one of these conditions and makes the diagnosis of adenomatous pituitary disease unlikely.[1]
AVP-D may develop as a complication of subarachnoid hemorrhage, meningitis, or encephalitis.
Systemic conditions that involve the pituitary stalk can cause AVP-D. These include Langerhans cell histiocytosis, sarcoidosis, and tuberculosis.[1][18][21]
A history of other autoimmune diseases, such as Hashimoto thyroiditis or diabetes mellitus type 1, should alert to an autoimmune process involving the hypothalamo-pituitary axis producing AVP-D.[29]
Hypercalcemia, hypokalemia, chronic kidney disease, renal sarcoidosis, and renal amyloidosis are recognized 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, an autosomal recessive, progressive neurodegenerative disorder.[37][39]
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
Physical exam
Severe volume depletion or hypernatremia 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), examination may show:
Signs of volume depletion: dry mucous membranes, reduced skin turgor, tachycardia, and postural hypotension.
Evidence of hypernatremia: symptoms and signs are nonspecific. Central nervous system (CNS) manifestations include irritability, restlessness, lethargy, muscle twitching, spasticity, and hyperreflexia. If hypernatremia is severe, delirium, seizures, and coma may be present.[55]
CNS exam
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., tumor, subarachnoid hemorrhage, meningitis, or encephalitis).
Visual failure with optic atrophy and sensorineural deafness may suggest Wolfram syndrome.[39]
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.[3] In children, growth and development are affected.[25][26]
AVP-D may be masked by coexisting adrenocorticotropic hormone deficiency and manifest when glucocorticoid replacement is started.[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 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 recognized that diabetes mellitus can coexist 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 ]
A 24-hour urine output of <3 L (or <50 mL/kg/24h) in an adult is very much against a diagnosis of AVP-D or AVP-R. A reduced urine osmolality (<300 mOsm/kg) in conjunction with high serum osmolality (>290 mOsm/kg) or elevated serum sodium strongly suggests AVP-D or AVP-R. An ability to concentrate urine (>600 mOsmol/kg) makes AVP-D or AVP-R unlikely. Patients with hyponatremia 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 been the standard, historical 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 analog 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 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 coexisting 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.
Failure to concentrate urine appropriately (thus indicating AVP-D or AVP-R) is confirmed by a final urine osmolality <300 mOsm/kg with corresponding plasma osmolality >290 mOsm/kg. This threshold is important in determining progression to the second phase of the test: AVP-analog stimulation to differentiate between AVP-D and AVP-R.
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 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.
The test has several problems. Patient acceptability is low; the protocol is resource intense; supervision after the AVP-phase is key; and the sensitivity and specificity are limited by the high prevalence of partial concentrating defects, meaning many test results are indeterminate. The test can only be interpreted in the setting of achieving an elevated plasma osmolality. 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.[56][57]
Hypertonic saline stimulation testing and measurement of copeptin
The water deprivation test 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 standardized osmolar stress. The direct measurement of AVP is problematic. The circulating half-life is short and immuno-platforms for measurement are not widely available. An alternative approach is to use copeptin as an alternative analyte to AVP. Copeptin is the c-terminal fragment of the larger AVP-precursor synthesized 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. Importantly, it is much more stable and much easier to develop as a sustainable direct measure of the AVP axis.
A baseline (without water deprivation or hypertonic saline-stimulation) copeptin level >21.4 pmol/L differentiates AVP-R from primary polydipsia and AVP-D with a 100% sensitivity and specificity.[58] A copeptin value of >4.9 pmol/L during graded hyperosmolar stimulation with a 3% sodium chloride infusion has a diagnostic accuracy of 96% in differentiating AVP-D from primary polydipsia.[57] The hypertonic saline test needs to be done under supervision in a department that is familiar with the test as it can cause side effects of thirst, nausea and headache. Arginine stimulation of copeptin may be used as an alternative to the hypertonic saline stimulation tests but is a less accurate test (74% vs. 96%).[59]
Subsequent investigations to establish the cause
Cranial imaging (pituitary MRI)
Should be ordered in all patients with AVP-D. Imaging modality of choice is magnetic resonance imaging. In normal individuals, 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 hormone in neurosecretory granules of the gland. The T1 "bright spot" is present in most normal subjects, but absent in nearly all patients with AVP-D. Sensitivity is thus high, while specificity is more limited.
Evidence of pituitary enlargement, including pituitary stalk thickness, may suggest the underlying pathology of AVP-D.[4][25][60]
Mixed solid and cystic components, with enhancement of the solid component and cyst wall, suggest a craniopharyngioma.
Repeat imaging is recommended at 6 and 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.[37] Wider features of Wolfram syndrome (diabetes mellitus, optic atrophy, sensorineural deafness) should prompt consideration of WFSI gene studies.[39]
AVP-R: this condition may occur in patients with loss-of-function mutations in the AVP signaling 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.[37]
Tumor 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][19]
In this population, serum and cerebrospinal fluid alpha-fetoprotein and beta-human chorionic gonadotropin may serve as markers for germ cell tumors and should be considered, although they do lack sensitivity, and more frequent neuroimaging is recommended.[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.[3]
Assessment includes measurement of pituitary hormones (growth hormone, prolactin, adrenocorticotropic hormone, thyroid-stimulating hormone, follicle-stimulating hormone, and LH), and the hormones from their target organs (insulin-like growth factor 1, cortisol, free thyroxine, total and free testosterone, estradiol).
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