History and exam
Key diagnostic factors
common
history of pituitary/hypothalamic disease
family history/genetic mutations
Arginine vasopressin (AVP) resistance may occur in patients with loss-of-function mutations in the AVP receptor pathway, which are inherited in an X-linked or autosomal-recessive pattern.[5][10][45] AVP-D may occur in patients with Wolfram syndrome (also called DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness] syndrome) and AVP-neurophysin gene mutations, inherited in an autosomal-dominant pattern.[39][41]
history of lithium therapy (or certain other drugs)
Lithium therapy is a well-established cause of arginine vasopressin resistance (AVP-R), with studies reporting its occurrence in up to 40% of patients receiving long-term lithium therapy, and some estimates suggesting rates as high as 85%.[9][10] Other drugs associated with AVP-R include demeclocycline, cisplatin, colchicine, gentamicin, rifampicin, and sevoflurane.[5][44]
history of autoimmune disorders
Arginine vasopressin deficiency (AVP-D) is associated with other endocrine autoimmune disorders. In one study, 26% of patients with AVP-D had an associated autoimmune disorder - most frequently Hashimoto's thyroiditis (16.7%) and diabetes mellitus type 1 (5.3%).[28] Systemic lupus erythematosus is also a potential cause.[3]
polyuria
increased thirst/polydipsia
Fluid intake increases to match renal water loss, leading to significant polydipsia.
Other diagnostic factors
common
uncommon
signs of volume depletion
If thirst is decreased (e.g., due to primary pathology, 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]
Signs include dry mucous membranes, poor skin turgor, tachycardia, hypotension, and, in severe cases, shock.
non-specific central nervous system symptoms of hypernatraemia
If thirst is decreased (e.g., due to primary pathology, 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]
Symptoms and signs of hypernatraemia are non-specific. They include irritability, restlessness, lethargy, spasticity, and hyper-reflexia. If severe, delirium, seizures, and coma may be present.[55]
visual field defects
May indicate a previous or existing pituitary mass.[3]
endocrine signs
In patients with previous functional pituitary macro-adenoma, there may be clinical signs of acromegaly or Cushing's syndrome (if not in remission). Postsurgical AVP-D may be associated with clinical hypopituitarism.
focal motor deficits
May be present due to previous or co-presenting intracranial pathology such as tumour, head injury, hydrocephalus, meningitis, or encephalitis.
sensorineural deafness and visual failure
May reflect additional components of Wolfram syndrome (also called DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness] syndrome), a progressive neurodegenerative disorder characterised by diabetes mellitus and optic atrophy, with varying frequency of arginine vasopressin deficiency and sensorineural deafness.[41]
skin lesions
Presence of papular rashes or ulcers may suggest systemic Langerhans' cell histiocytosis, which can cause AVP-D.
Similarly, the presence of erythema nodosum may suggest sarcoidosis as a cause of AVP-D or AVP-R.
Risk factors
strong
pituitary surgery
Pituitary or para-pituitary surgery is a common cause of arginine vasopressin deficiency (AVP-D).[51] Pituitary adenomas do not themselves present with AVP-D; the syndrome only manifests after surgical intervention. If AVP-D occurs in the presence of a sellar mass, an alternative diagnosis, such as craniopharyngioma, germinoma, pituitary metastases, or a granulomatous process should be considered.[3] AVP-D after pituitary surgery may be transient or permanent. Rarely, there may be a classical triple-phase response: an acute initial AVP-D, followed by a transient antidiuretic phase (syndrome of inappropriate antidiuresis), subsequently progressing to permanent AVP-D.[12]
craniopharyngioma
In contrast to most intracranial tumours, AVP-D is common at presentation in patients with craniopharyngioma (8% to 35%). Incidence increases postoperatively (70% to 90%).[13]
There may also be associated thirst abnormalities, either as a consequence of more extensive hypothalamic involvement of the tumour or as a consequence of intervention.[14]
pituitary stalk lesions
Lesions involving the pituitary stalk are recognised causes of arginine vasopressin deficiency (AVP-D).[4][24]
Pituitary stalk involvement is common in Langerhans' cell histiocytosis (LCH). In one study, AVP-D was reported in up to 24% of patients with paediatric-onset LCH.[17] Other conditions leading to pituitary stalk involvement and AVP-D include germinoma, intracranial metastases (particularly from breast or lung primaries), lymphoma/leukaemia, granulomatous disease (e.g., sarcoidosis and tuberculosis), lymphocytic infundibulohypophysitis, and immunoglobulin G4-related disease.[1][3][18][19][20][21][22][23][24][25]
traumatic brain injury
congenital pituitary abnormalities
Congenital malformations involving the pituitary or hypothalamus may be associated with AVP-D.[40]
use of certain drugs
Lithium therapy is a well-established cause of arginine vasopressin resistance (AVP-R), with studies reporting its occurrence in up to 40% of patients receiving long-term lithium therapy, and some estimates suggesting rates as high as 85%.[9][10] Other drugs associated with AVP-R include demeclocycline, cisplatin, colchicine, gentamicin, rifampicin, and sevoflurane.[5][44]
Arginine vasopressin deficiency is less commonly caused by drugs. It has been reported in association with phenytoin and temozolomide (an oral chemotherapy drug used primarily to treat certain types of brain tumours).[32][33]
hypophysitis
AVP-D is associated with hypophysitis either in isolation or in combination with anterior pituitary hormone dysfunction.[52]
autoimmune disease
Arginine vasopressin deficiency (AVP-D) is associated with other autoimmune endocrine disorders - most frequently Hashimoto's thyroiditis (16.7%) and diabetes mellitus type 1 (5.3%).[28] Systemic lupus erythematosus is also a potential cause.[3]
Autoantibodies to arginine vasopressin-secreting cells (AVPcAb) have been reported in 33% of patients with idiopathic (non-structural) AVP-D.[28]
family history/genetic mutations
There are familial (inherited) forms of both arginine vasopressin deficiency (AVP-D) and arginine vasopressin resistance (AVP-R). AVP-R may occur in patients with loss-of-function mutations in the AVP receptor pathway.[5][10] Most common are mutations in the AVPR2 receptor, inherited in an X-linked recessive pattern. Aquaporin-2 water channel gene mutations (autosomal recessive) and urea transporter-B mutations also produce AVP-R.[5][10][39]
Familial AVP-D accounts for approximately 1% to 5% of all cases of AVP-D. It is usually an autosomal dominantly inherited condition due to a mutation in the AVP-NPII gene located on chromosome 20p135. This condition often has many family members presenting with clinical AVP-D early on in life.[39] AVP-D may also occur as a component of Wolfram syndrome (also called DIDMOAD [diabetes insipidus, diabetes mellitus, optic atrophy, and deafness] syndrome), an autosomal recessive, progressive neurodegenerative disorder characterised by diabetes mellitus and optic atrophy, with varying frequency of AVP-D and sensorineural deafness.[41]
weak
pregnancy
Pregnancy is associated with a number of changes in salt and water regulation.[46] There is a fourfold increase in metabolic clearance of AVP in pregnancy, due to placental production of vasopressinase/oxytocinase. This can un-mask previously partial arginine vasopressin deficiency (AVP-D).[6][47] Transient gestational AVP-D has been reported in patients with pre-eclampsia, HELLP (haemolysis, elevated liver enzymes, and low platelet count) syndrome, and acute metabolic dysfunction-associated steatotic liver disease, where impaired hepatic degradation of vasopressinase is a contributing factor.
subarachnoid haemorrhage
renal sarcoidosis
Recognised cause of AVP-R.[20]
renal amyloidosis
Recognised cause of AVP-R.[5]
hypercalcaemia or hypokalaemia
Recognised cause of AVP-R.[5]
previous central nervous system infections
Coronavirus 2019 (COVID-19) infection
COVID-19 has been linked to rare instances of new-onset arginine vasopressin deficiency in a small number of case reports.[3][34][35] Proposed mechanisms include direct viral invasion of the hypothalamus or posterior pituitary via ACE2 receptors, immune-mediated inflammation damaging AVP-producing neurons, and vascular or hypoxic injury to the neurohypophyseal axis during severe illness.[36][37] In some cases, the condition appears transient, suggesting reversible functional disruption.
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