arginine vasopressin ( avp ) is an antidiuretic hormone which is synthesized in the magnocellular neurons of the supraoptic ( son ) and paraventricular nuclei ( pvn ) in the hypothalamus . avp is transported to the posterior pituitary through the axons , released into the systemic circulation , and plays a pivotal role in water balance by promoting reabsorption of free water through the v2 receptor in kidney . the release and synthesis of avp are mainly regulated by plasma osmolality ( or serum na ) in physiological conditions . the osmoregulation of the avp neuron system is so precise that only 12% increases in serum na levels significantly stimulate its release as well as the transcription of avp gene in the son and pvn . serum na levels are thus maintained around 140 meq / l , the threshold level for avp release . the deficiency of avp leads to hypotonic polyuria , a disorder called neurohypophysial or central diabetes insipidus ( hereafter , we use cdi as the abbreviation ) . water intake also increases in order to maintain water balance in patients with cdi , as long as their thirst sensation remains intact . in this review , most causes of cdi are acquired , and its prevalence of cdi is reportedly 1:25,000 . 
 table 1 indicates the etiology of 165 japanese patients with cdi we reported previously . the most frequent cause of cdi is the tumors in the central nervous system ( cns ) including craniopharyngioma and germ cell tumors , which could damage the avp neuron system . cdi is also caused by inflammatory diseases such as lymphocytic infundibulo - neurohypophysitis ( linh ) and igg4-related disease . , polyuria appears in the first 2 days after surgery and sometimes resolves spontaneously , although it could persist permanently if avp neurons are damaged substantially . idiopathic cdi , 13% of total cdi in table 1 , is diagnosed when the causes of cdi are unclear . it is of note that linh has been sometimes regarded as idiopathic cdi in some studies . this is probably because linh is reported to be a possible underlying cause of idiopathic cdi . this subclass of cdi is called familial neurohypophysial diabetes insipidus ( fndi ) , which is inherited mostly in an autosomal dominant mode . more than 80 mutations that cause fndi have been reported so far , and they are mainly located in the coding region of neurophysin ii , a carrier protein of avp , in the gene locus ( table 2 ) . mutations causing fndi * , mutations affecting the initiator atg are predicted to result in translation initiation at an alternative downstream atg ( codon 5 ) , causing a deletion of the first 4 amino acid residues .  , mutations associated with autosomal - recessive inheritance of fndi . , 10,396 base pair deletion involving the majority of the avp gene as well as its regulatory sequences in the intergenic region between the avp and the oxytocin gene . if splicing of intron 2 is affected , the entire ( in - frame ) intron is inserted into the mrna leading to an insertion of 58 amino acids into the avp protein ( p. ? ) . if splicing is not affected , this mutation causes to change codon 108 to a premature termination codon ( p. e108x ) . cdi is characterized by hypotonic polyuria accompanied by polydipsia , as long as the thirst sensation is intact . daily urine volumes exceed 3 liters in most cases . daily water intake , which could be estimated by asking the subjects how many cups of water they take every day , is almost equal to daily urine volumes . if daily water intake seems to be less than 2 liters , the subjects are unlikely to have cdi . it is also important to ask the subjects how often they urinate and drink water at night , because only daytime polydipsia and polyuria suggest psychologic polydipsia rather than cdi . final diagnosis of cdi is made by confirming that avp release is hampered in response to increases in plasma osmolality or serum na levels . for this reason , either injection of hypertonic saline or the water restriction test is performed . in the hypertonic saline examination , 5% nacl at the rate of 0.05 ml / kg body weight ( bw ) /min is injected intravenously for 2 hours , and the serum na and plasma avp levels are measured before and every 30 minutes after starting the injection . the serum na levels usually increase approximately by 10 meq / l , and plasma avp levels are increased in proportion to the increases in serum na levels in normal subjects . in contrast , increases in avp release are blunted or even abolished in patients with cdi ( figure 1 ) . to perform this examination , it is essential to use a sensitive assay for plasma avp . plasma avp and serum na levels in response to hypertonic saline injection . in normal subjects , plasma avp levels increase in proportion to increases in serum na levels . in cdi patients , no sensitive assays for plasma avp are available , the water restriction test is performed . the subjects are deprived of water and food for about 6 hours or until their bw is decreased by 3% . in normal subjects , in contrast , urine osmolality remains to be below 300 mosm / kg during the test in cdi patients . injection of pitressin ( vasopressin ) at the end of the test could differentiate nephrogenic di from cdi : urine osmolality increases in response to pitressin in patients with cdi but not in those with nephrogenic di . the high intensity in posterior pituitary in t1-weighted mri images , which reportedly reflects the stock of pituitary avp , is observed in normal but not cdi subjects . however , as the avp stock in the posterior pituitary could be decreased under chronically dehydrated conditions , the lack of the high signal in t1-weighted pituitary mri images is not specific to cdi . pituitary mri is also useful for the differential diagnosis of primary and secondary cdi . in case there is no abnormality except for the lack of the high signal in t1-weighted images , the subjects are diagnosed as idiopathic cdi . however , the follow - up of the imaging is necessary , particularly in children , since some abnormalities such as tumors in the cns may appear later on . due to the lack of avp action on v2 receptors in kidney , patients with cdi show hypotonic polyuria and polydipsia . the amount of daily urine volume as well as water intake could exceed 10 liters when avp release is almost completely abolished . normal subjects feel thirsty when serum na levels exceed 145 meq / l , while the threshold of serum na levels for avp release is around 140 meq / l in cdi patients , in whom the action of avp is lacking . thus , cdi patients consume water until their thirst sensation ceases , but they will soon feel thirsty because serum na levels exceed 145 meq / l again due to the lack of avp action . if the function of osmoreceptors in hypothalamus is also lost , the patients would not feel thirsty even if the serum na levels exceed 145 meq / l . this is called  masked di ,  and substitution of adrenocortical hormones leads to increases in urine volume in patients with cdi accompanied by adrenal insufficiency . while several mechanisms have been suggested for masked di , one possibility is that avp release , which is usually inhibited by adrenocortical hormones , is stimulated from the residual avp neurons in cdi patients with adrenal insufficiency . however , it is still controversial whether or not glucocorticoid receptors are expressed in the avp neurons . fndi patients are born with normal water balance , but manifest progressive polyuria and polydipsia several months or years after birth . the analyses of animal models for fndi have demonstrated that accumulation of mutant avp precursors in the endoplasmic reticulum ( er ) causes er stress and dysfunction of the neurons , which finally lead to loss of avp neurons . this is consistent with autopsy studies which showed that magnocellular neurons were lost in patients with fndi . the desmopressin formula is either intranasal liquid , intranasal spray , or tablets . in japan , an oral disintegrating tablet ( odt ) was approved for the treatment of cdi in 2012 , and the qol of cdi patients has reportedly been improved by odt . our study also showed that the incidence of hyponatremia in cdi patients treated with desmopressin is decreased after the switch from the nasal formula to odt . this is probably due to the fact that the absorption and efficacy of odt are more stable than those of the nasal formula , making it easier to determine the required dose of desmopressin . nevertheless , one should be aware that there is still a high incidence of hyponatremia in cdi patients treated with desmopressin , and it is safe to start the treatment with a low dose of desmopressin . the ideal bw for water balance should be determined based on the serum na levels ( bw is considered to be ideal when serum na levels are within normal ranges ) , but this could vary over time and should be assessed periodically . the basal volume of water intake ( for example , 1 liter / day ) and the required dose of desmopressin ( for example , 60 g odt desmopressin twice a day ) to maintain the ideal bw should also be determined . however , one should recall that bw could substantially change from day to day in patients , and the scale of water intake must be set based on the bw changes . for example , if the bw is 58 kg in adipsic cdi patients whose ideal bw has been determined to be 60 kg , 2 kg water has been lost . in this situation , 2 liters of water should be consumed in addition to the basal volume ( 1 liter ) of daily water intake ; that would mean that patients must drink 3 liters of water on the day , but it could be difficult for adipsic patients to consume such a volume of water , given that they do not sense thirst . the prognosis of cdi due to tumors or inflammation depends on that of the primary diseases . on the other hand , the prognosis of idiopathic cdi patients is considered to be comparable to that of subjects without cdi , as long as the patients can drink water as necessary . however , the adipsic cdi patients are associated with significant morbidity , and the incidence of serious infections requiring hospitalization and the risk of death have been shown to be higher in adipsic compared to non - adipsic cdi patients . the etiology has been clarified in most cdi patients . while most cdi patients are well treated with desmopressin , controlling water balance in adipsic cdi patients