Synthesis and Secretion

Arginine vasopressin (AVP) is a polypeptide that contains nine amino acids, with a disulfide bridge between cysteine residues, and considerable structural homology with oxytocin, which also is secreted from the posterior pituitary (Fig. 14-1).¹ Vasopressin is synthesized predominantly in the magnocellular neurons in the paraventricular (PVN) and supraoptic (SON) nuclei of the anterior hypothalamus (Fig. 14-2). The cell bodies of the vasopressinergic neurons in the PVN and SON have axonal projections that connect to the posterior pituitary gland.

In addition to magnocellular neurons, which project from the SON and the PVN to the posterior pituitary, parvocellular vasopressinergic neurons are present in the PVN and the suprachiasmatic nucleus.² These smaller neurons project via the median eminence to the portal vascular system of the anterior pituitary while secreting vasopressin and corticotropin-releasing factor (CRF); they stimulate secretion of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. Some parvocellular vasopressinergic neurons also project from the PVN to the forebrain, brain stem, and spinal cord. Vasopressin is released into the central nervous system, where it acts as a neurotransmitter and/or a neuromodulator.³

The gene that encodes the AVP precursor is expressed mainly in the hypothalamus but also in other tissues, including adrenal glands, gonads, cerebellum, and pituicytes in the posterior pituitary. It is structurally closely related to the gene that codes for the oxytocin (OT) precursor, which is expressed in different populations of hypothalamic magnocellular neurons. The vasopressin and oxytocin genes are closely linked in a tail-to-tail orientation on chromosome 20 with an intergenic region of 12 kb.⁴ Significant posttranslational processing is needed to form the mature hormone. The posttranslational product prepro-AVP-NPII is the precursor from which AVP is derived.⁴ The precursor consists of a signal peptide, AVP, neurophysin II (NPII; 95 amino acids), and a glycopeptide, copeptin (39 amino acids).

Neurophysin II is cleaved from prepro-AVP-NPII but remains complexed together with AVP before it is secreted into the bloodstream by exocytosis. Vasopressinergic neurons open voltage-gated calcium channels in nerve terminal membranes. This transient calcium ion influx results in fusion of neurosecretory granules with the nerve terminal membrane, as well as release of AVP and NPII in equimolar amounts into the circulation.⁵ Copeptin, although of unknown biological significance, may be a stable indirect marker of AVP release.

Magnocellular neurons in the supraoptic and paraventricular nuclei synthesize vasopressin within their cell bodies. The hormone is carried within neurosecretory granules down the predominantly unmyelinated axons of the magnocellular neurons, in the supraoptic-hypophyseal tract, at a speed of 2 mm per hour. The precursor undergoes successive cleavage by basic endopeptidases.⁶ These axons terminate in the posterior pituitary, which is rich in fenestrated capillaries.

Cellular Action of Vasopressin

Vasopressin binds to seven transmembrane, G-protein–coupled receptors on the plasma membrane of target cells. Three subtypes of vasopressin receptor exist (V1-V3) with distinct distribution, actions, and signal transduction.7,8

Osmoregulation of Vasopressin Release

Plasma osmolality in healthy man varies by only 1% to 2% in physiologic conditions where there is free access to water. This precise regulation of plasma osmolality is maintained by the homeostatic process of osmoregulation.¹⁸

Changes in plasma osmolality are detected by specialized osmoreceptor cells in the anterior hypothalamus (see Fig. 14-2). Fenestrations in the blood-brain barrier cause the magnocellular cells of the circumventricular organs—the subfornical organ and the organum vasculosum lamina terminalis—to be bathed in plasma. Changes in plasma osmolality cause these hypothalamic nuclei to depolarize, sending neural signals, via the nucleus medianus, to the supraoptic and paraventricular nuclei. Elevation in plasma osmolality causes depolarization of these nuclei, leading to increased synthesis of AVP and secretion of AVP from the posterior pituitary. The osmoreceptor cells are solute specific, in that they respond vigorously to changes in plasma sodium concentration but less so to variations in blood urea.¹⁹ They respond to mannitol but are completely insensitive to changes in blood glucose concentration in experimental situations.

A linear relationship has been noted between plasma osmolality and plasma AVP concentrations throughout the physiologic range of plasma tonicity.20–22 If plasma concentrations are lowered by excessive ingestion of hypotonic fluid to below 280 to 285 mOsm/kg, secretion of AVP is suppressed, and plasma concentrations of the hormone are undetectable on radioimmunoassay measurement. In the absence of AVP-mediated water reabsorption from the kidney, hypotonic polyuria develops.²² The increase in free water clearance allows plasma osmolality to rise into the normal range. If plasma osmolality rises, owing to dehydration, plasma concentrations of AVP increase in proportion to the rise in plasma osmolality. The action of AVP in concentrating the urine and allowing reabsorption of water restores plasma osmolality to normal. This homeostatic process occurs continuously to maintain plasma osmolality within a narrow reference range. The relationship between plasma AVP concentration and urine osmolality is shown in Fig. 14-4.

The development of sensitive radioimmunoassays has allowed the nature of this relationship to be studied experimentally. When intravenous infusion of hypertonic sodium chloride solution is used to increase plasma osmolality in healthy volunteers, plasma AVP can be shown to increase in a linear fashion. Application of linear regression analysis to the data shows that a direct correlation defines the relationship between plasma osmolality and plasma AVP concentration (Fig. 14-5). The qualitative relationship is expressed by the following equation:

where pAVP indicates plasma AVP concentration, and pOsm indicates plasma osmolality.²³

This mathematical formula describes two important physiologic characteristics of the relationship between plasma osmolality and plasma AVP that are clinically relevant. The first of these is the osmotic threshold for AVP release, which is defined by the abscissal intercept of the regression line. At a mean plasma osmolality of 284 mOsm/kg, plasma AVP is secreted, with increments in secretion as plasma osmolality rises. This represents the “set point,” or the osmotic threshold for AVP release, which is identical in man to the osmotic threshold for the onset of thirst.²³ This is an important physiologic concept, as hypotonic polyuria develops when plasma osmolality is suppressed by water ingestion to concentrations below this “set point.” Therefore, AVP detectable in the plasma by radioimmunoassay at plasma osmolalities below this is, by definition, “inappropriately” elevated. Measurements of plasma AVP with ultrasensitive cytochemical methods at plasma osmolalities below the physiologic threshold have led to suggestions that secretion cannot be completely suppressed by hypotonicity,²⁴ although the very low concentrations demonstrated experimentally could equally represent incomplete clearance of pre-secreted AVP.

The slope of the regression line, which represents the change in plasma AVP concentration per unit change in plasma osmolality, is the second important characteristic of the formula. This defines the sensitivity of the osmoreceptor-AVP releasing unit. Steeper slopes indicate a larger rise in plasma AVP concentrations after osmotic stimulation. Shallow slopes indicate lower rates of AVP secretion in response to hyperosmolality; a pathologic example of this can be seen in partial hypothalamic diabetes insipidus.²⁵

In a few rare cases, complete disconnection of AVP-secreting neurons from their osmoreceptors has been described. The pathologic abnormality is persistent low-grade AVP release, despite plasma osmolalities that may fall below the osmotic threshold.²⁶ AVP secretion can be increased to above this “basal” rate by stimulation of osmoreceptors, but secretion is never switched off entirely. It is hypothesized that some cells exert an inhibitory effect on AVP release, and if these cells malfunction, AVP secretion is abnormally continuous.

The osmotic threshold and sensitivity of AVP release vary significantly between individuals, but repeat testing has shown good reproducibility of these parameters within individuals.²⁷ Studies in twins have suggested that the characteristics of the osmoregulatory line may be genetically determined, given that they are similar in monozygous but not dizygous twins.²⁸

Although physiologic control of AVP secretion and thirst is almost entirely osmotic, the switch-off of the two is nonosmotic and is triggered by the act of drinking. In studies in healthy men who have been rendered hyperosmolar by hypertonic saline infusion²⁹ or by dehydration,³⁰ drinking is associated with an immediate fall in plasma AVP and thirst, before any changes in plasma osmolality can be measured. The fall in plasma AVP is so rapid that it mimics the half-life of AVP,²⁹ suggesting that a neuroendocrine reflex, stimulated by oropharyngeal distention, switches off AVP secretion.

The conventional relationship between plasma osmolality and plasma AVP concentration is altered in a number of physiologic and pathophysiologic situations. Pregnancy causes a lowering of the threshold for AVP secretion in both rats³¹ and humans,³² which is responsible for the fall in basal plasma sodium concentration during pregnancy. The sensitivity of the osmoregulatory line remains unchanged. The mechanism is unclear but may be related to increased plasma concentrations of human chorionic gonadotropin (hCG). In the luteal phase of the ovulatory cycle, a small but significant decrease in plasma osmolality also occurs as a result of downward resetting of the osmotic thresholds for thirst and AVP release.³³

Normal physiologic aging is associated with complex changes in osmoregulation.³⁴ Basal circulating AVP concentrations increase with age, and the AVP response to osmotic stimulation has been shown to be enhanced in comparison with that in younger subjects.^35,36 Thirst, as measured by visual analogue scales, is attenuated, however, and measured water intake after osmotic stimulation intake is reduced.³⁷ This makes elderly humans more vulnerable to hypernatremia; many elderly patients in long-term care institutions exhibit permanent hypernatremia, although cognitive impairment may contribute to reduced thirst in these individuals.³⁸

Osmoregulation in diabetes mellitus seems normal,³⁹ even in the presence of hypernatremia,⁴⁰ with preserved solute specificity of both AVP release and thirst; hyperglycemia stimulates neither thirst nor AVP secretion. Chronic hyperglycemia renders the renal tubules resistant to the antidiuretic effects of AVP, however, as the result of failure of recruitment of aquaporin-2.⁴¹ Improved glycemic control reverses the state of partial nephrogenic diabetes insipidus.⁴¹ Survivors of HONK, however, show typical osmoregulatory changes of aging, with exaggerated AVP secretion and attenuated thirst in response to dehydration.⁴²

Baroregulation of Vasopressin Release

Although small variations in plasma osmolality can have profound effects on AVP secretion, physiologic fluctuations in blood pressure have almost no effect on plasma AVP secretion. However, pathophysiologic falls in both blood volume and pressure can stimulate AVP secretion. Although small falls in arterial blood pressure (on the order of 10%) have been shown to slightly increase plasma AVP concentrations (see Fig. 14-5), larger falls of 20% to 30% are required to stimulate sufficient AVP to exert a compensatory pressor effect.^43,44 This makes teleologic sense as falls in blood pressure of up to 10% are common during a daily cycle, and if AVP were stimulated by these small falls, humans would be in a permanent state of antidiuresis. The relationship between blood pressure and plasma AVP is shown in Fig. 14-6.

The baroreceptors are situated in the cardiac atria, the carotid sinus, and the aortic arch. They exert a tonic inhibitory effect on AVP secretion in normal circumstances, but when they are unloaded during hypotension or hypovolemia, they can stimulate very high plasma concentrations of AVP via pathways that are separate from the osmoreceptors. The relation between blood pressure and AVP is exponential rather than linear and can be modified by neurohumoral influences such as atrial natriuretic peptides, which inhibit AVP responses, and norepinephrine, which augments baroregulatory AVP responses.⁴⁵ Baroregulatory inputs also modify osmotic AVP secretion, in that hypovolemia augments the AVP response to hypernatremia.^46,47

Other Mechanisms Regulating Vasopressin Release

In addition to osmotic and baroregulatory stimuli, AVP secretion occurs in response to nausea,48,49 manipulation of abdominal contents at surgery,⁵⁰ and hypoglycemia.⁵¹ All of these secretagogues stimulate AVP secretion independently of the osmotic pathways.

Hypothalamic Diabetes Insipidus

HDI (also known as neurogenic, central, or cranial DI) occurs when AVP secretion is insufficient to prevent the development of a hypotonic diuresis, such that the patient presents with polyuria and nocturia. The lesion in the vast majority of cases spares the thirst mechanism⁵³; therefore, because thirst appreciation is intact, patients respond to the polyuria with appropriate polydipsia. The increase in fluid intake is nearly always sufficient to maintain normonatremia; hypernatremia in which fluid is freely available should always raise the suspicion of associated thirst abnormalities. The AVP deficiency may be complete, with no detectable plasma AVP, or partial, where AVP is detectable in the plasma at low concentrations inappropriate to the ambient plasma osmolality.

HDI is rare in the general population with an estimated prevalence of 1:25,000 but is common in certain subgroups, such as patients undergoing pituitary surgery, or transiently in other forms of neurosurgical intervention.

Most cases of HDI are acquired during adult life, and the most common cause of DI in most endocrine practices is surgery for pituitary tumors. Pituitary adenomas rarely cause DI, and when a pituitary mass is associated with polyuria, then craniopharyngioma, granuloma, and hypophysitis are far more likely diagnoses.

DI occurs in the immediate postoperative period in 18% to 30% of cases,54–57 with most cases presenting in the first 2 days following surgery. The most common natural history is spontaneous resolution over the next 2 to 5 days. The pathophysiology of acute transient DI is thought to be surgical contusion injury to the magnocellular neurons projecting from the supraoptic and paraventricular nuclei to the posterior pituitary. In some patients however, DI persists and AVP deficiency becomes permanent. Most neurosurgical series report a low incidence of 1% to 8% for permanent DI, following transsphenoidal surgery.^54,56–58 Many published studies are retrospective, however, and use polyuria alone as the criteria for diagnosis of DI. We found that formal water deprivation testing identified permanent DI in 30% of patients who had transcranial surgery for pituitary adenoma and much higher figures of over 90% following craniopharyngioma surgery.⁵⁵

In a small minority of patients, post-hypophysectomy DI follows the triple phase response. Initially, classical postoperative DI presents in the first 2 days following surgery. However, after 4 to 8 days of hypotonic polyuria, urine output drops and plasma sodium begins to fall, even after discontinuation of desmopressin therapy. This second, antidiuretic phase is characterized by a rise in plasma AVP concentrations, presumably from uncontrolled release of pre-stored peptide from damaged magnocellular neurons. If hypotonic intravenous fluids continue to be administered, the fall in plasma sodium concentration can be abrupt. The antidiuretic phase of the triple phase response usually lasts 5 to 7 days, but considerable variation is noted, from 2 to 14 days, before progression to the final phase, the development of permanent DI. It is thought that permanent DI occurs when gliosis of damaged neurons prevents further AVP release.

The major factor influencing the risk of developing diabetes insipidus following pituitary surgery is tumor type. Craniopharyngioma is associated with preoperative DI, but in addition, surgical intervention is far more commonly associated with the development of DI than is surgery for any other intracranial tumor.⁵⁵ Surgery for ACTH-secreting pituitary adenomas has been associated with a higher risk of developing DI in a number of series.^54,56,58 Data from the literature are conflicting regarding the influence of tumor size on the risk of postoperative diabetes insipidus. Although pituitary adenomas rarely cause HDI, metastatic deposits in the hypothalamus, or more often the pituitary stalk, can result in HDI. Metastatic deposits usually have no endocrine effects, even when they are found in the stalk or the pituitary itself, but some, particularly from carcinoma of the breast or bronchus, produce HDI. Other tumors such as germinoma, pinealoma, and parasellar meningioma can cause HDI. It is interesting to note that although radiotherapy for nonpituitary cranial tumors commonly causes anterior pituitary dysfunction, it does not seem to cause DI.⁵⁹

Lymphocytic infiltration of the neurohypophysis (infundibulo-neurohypophysitis), recognized by a thickened pituitary stalk and inflammatory infiltrates of T lymphocytes and plasma cells with eosinophils, is a well-described cause of HDI.⁶⁰ HDI is present in up to 30% of adult patients with Langerhans’ cell histiocytosis (LCH).⁶¹

Idiopathic DI is diagnosed less often, as better imaging techniques have been introduced and awareness of autoimmune causes has increased.62,63 It has been estimated that one third of patients previously diagnosed to have idiopathic HDI may an autoimmune origin of the condition. The characteristics of autoimmune DI include the presence of circulating antibodies against AVP-secreting cells, young age of onset, and thickened pituitary stalk T1-weighted magnetic resonance imaging (MRI).⁶⁴ Patients with autoimmune DI have an increased incidence of other organ-specific autoimmune endocrine disease, particularly thyroid disease.

Traumatic brain injury causes acute diabetes insipidus in 20% of cases,⁶⁵ some of which result in a triple phase response similar to that seen after pituitary surgery. DI following brain injury is nearly always transient,⁶⁶ however, and only 7% of long-term survivors of head injury have permanent DI when formally tested with water deprivation.⁶⁷

Sheehan’s syndrome is now rare and is not usually associated with HDI, even when anterior hypopituitarism is widespread, but maximal urine-concentrating ability is impaired in some patients.⁶⁸ HDI can occasionally occur in normal pregnancy as the result of increased activity of circulating vasopressinase, the placental aminopeptidase.⁶⁹ Symptoms resolve post partum. The actions of vasopressinase can unmask partial HDI in patients with pituitary disease or can worsen symptoms in undiagnosed partial HDI. HDI in pregnancy must be differentiated from the transient NDI that is seen very occasionally.⁷⁰

Familial HDI is extremely rare. Autosomal dominant HDI (adHDI) is associated with loss-of-function mutations in the AVP gene, resulting in the production of a folding-incompetent peptide precursor that accumulates in the secretory pathway apparatus of magnocellular neurons.71,72 This mutant precursor is responsible for an autophagocytic process that causes progressive damage and loss of VP neurons. A single mutant allele is sufficient for this process to occur. Most mutations affect exons 1 and 2 of the AVP gene.^73–75 Familial HDI almost always presents in childhood.⁷⁶

The Wolfram, or DIDMOAD, syndrome (diabetes insipidus, diabetes mellitus, optic atrophy, and deafness) is a rare autosomal recessive, progressive neurodegenerative disorder characterized by the association of HDI with diabetes mellitus, optic atrophy, and bilateral sensorineural deafness, although other manifestations may include gonadal failure, renal outflow tract dilatation (secondary to reduced nerve fibers in the bladder wall), and progressive ataxia with brain stem atrophy.⁷⁷ The syndrome is associated with premature death, usually due to ascending renal tract infection secondary to atonic bladder and hydronephrosis. Although DI is often reported to occur in only one third of cases, in one series where careful testing with AVP responses to hypertonic saline was performed, subnormal responses were seen in all patients.⁷⁸ WS is associated with loss-of-function mutations in the WFSI gene on Ch.4p16.1, which encodes an 890 amino acid glycoprotein (wolframin) found in the endoplasmic reticulum. An additional locus for WS has been identified recently at Ch.4q22-24, suggesting that the syndrome may be genetically heterogeneous.⁷⁹

Nephrogenic Diabetes Insipidus

Nephrogenic diabetes insipidus (NDI) occurs when renal resistance to the antidiuretic effects of VP allows hypotonic diuresis to develop. An outline of potential causes is given in Table 14-1. Lithium therapy is the most common cause of NDI in clinical practice, occurring in up to 30% of patients. Although polyuria usually disappears with cessation of treatment, a minority of patients develop interstitial nephritis, and permanent NDI occurs. Hypokalemia and hypercalcemia can produce acquired NDI, which is reversible with correction of the metabolic abnormality. Poorly controlled diabetes mellitus causes renal resistance to AVP, which seems to be due to failure to recruit aquaporin-2. The reversibility of the metabolic causes of NDI shows how the generation of aquaporins can be vulnerable to metabolic and pharmacologic insults.

Familial NDI is rare. X-linked recessive familial NDI (X-FNDI) is caused by inherited loss-of-function mutations in the V2-R. More than 70 different mutations have been described, affecting all aspects of receptor physiology, including expression, ligand binding, and G protein coupling. A vast majority cause complete loss of function and present in infancy, although some mutations are associated with partial loss of function.⁸⁰ A minority of FNDI families have autosomal recessive (AR-FNDI), loss-of-function mutations of the gene encoding AQP2. Most mutations occur in the region of the gene that encodes the transmembrane domain of the water channel protein. Other kindreds have been described with an autosomal dominant NDI (AD-NDI) caused by loss-of-function mutations in AQP2 affecting the carboxyl-terminal intracellular domain of the protein. NDI is expressed in these kindreds because the protein product of the mutant allele forms mixed oligomers with the product of the wild-type allele, resulting in sequestration within the Golgi or mistargeting to the basolateral rather than the apical membrane in a dominant negative manner.^81,82

Dipsogenic Diabetes Insipidus

Dipsogenic diabetes insipidus (DDI) occurs when excessive fluid intake lowers plasma osmolality to levels below the osmotic threshold for vasopressin secretion.⁸³ In the absence of circulating AVP, hypotonic polyuria develops. Many patients seem to have no underlying illness, but careful osmoregulatory studies have identified a number of abnormalities of thirst regulation. Patients typically have a low osmotic threshold for thirst, which compels them to drink, even when plasma osmolality is lowered below the usual physiologic thirst threshold. In addition, they have an exaggerated thirst response to osmotic challenge and an inability to suppress thirst in response to drinking, so the volume of fluid drunk is in excess of that required for normal hydration.⁸⁴ Some forms of DDI are associated with psychiatric disorders, and up to 20% of patients with chronic schizophrenia have DDI. If these patients are simultaneously prescribed drugs that can cause syndrome of inappropriate antidiuretic hormone secretion (SIADH), hyponatremia is inevitable and occasionally severe. Rarely, the problem may be associated with irritative structural abnormalities in the hypothalamus or posterior pituitary, such as hypothalamic sarcoidosis or craniopharyngioma, but usually brain imaging is normal.

Investigation of Diabetes Insipidus

A careful history is always valuable in the investigation of a polyuric patient. Although the history is less often diagnostic than in other conditions, useful clinical clues can be obtained. Daytime polyuria without nocturia is a pointer toward dipsogenic DI. Frequent passage of small volumes of urine may suggest prostatism, urinary tract infection, or bladder instability. A history of lithium or diuretic therapy is relevant. Knowledge that a sellar mass is present raises the diagnosis of craniopharyngioma or germinoma. A strong family history of autoimmune thyroid disease might suggest an autoimmune origin.

Initial investigations should aim to confirm that the patient is polyuric; 15% of patients who are referred to our service for investigation of polyuria have normal urine volumes, with frequency of micturition due to urinary tract disease. A 24-hour urine volume less than 3 liters makes osmotic studies unnecessary. Simple ambulatory investigations include electrolytes, calcium, midstream specimen of urine (MSU), and urinalysis; if the patient does not have glycosuria, polyuria is not due to diabetes mellitus. Clinic plasma and urine osmolality are rarely diagnostic unless the urine osmolality exceeds 700 mOsm/kg, at which point further investigation is not necessary. Urine osmolality is low in all three forms of DI. However, an elevated plasma osmolality is more likely with HDI or NDI, whereas a plasma osmolality at the low end of the reference range is suggestive of DDI.

In most patients, it is necessary to proceed to a water deprivation test.⁵² This is a two-step test of osmoregulatory function. The first step consists of an 8-hour period of dehydration. The normal physiologic response is to respond to the rise in plasma osmolality with secretion of AVP and concentration of urine to more than 750 mOsm/kg. Theoretically, patients with DDI have a normal osmoregulatory mechanism and should respond to dehydration with appropriate urine concentration. In the simplest use of this test, therefore, the key measurement is final urine osmolality, and the result answers the key question, “Does the patient have true DI, or not?” In patients who are being investigated for post-hypophysectomy HDI, only this step is needed to make the diagnosis.

The second step is the response to desmopressin. Urine osmolality is measured at intervals after intramuscular desmopressin; in patients with HDI, a normal concentrating response should occur, with a rise in urine osmolality to >750 mOsm/kg. In contrast, patients with NDI will fail to respond to desmopressin. Step 2 therefore involves distinguishing between HDI and NDI.

In practice, the water deprivation test does not always produce straightforward results. Surreptitious water intake can give spurious results, so the test should be undertaken with strict supervision; results are best expressed in units and are optimal when attained by the clinician who has experience in performing the test. Partial forms of HDI and NDI cannot be differentiated from DDI.⁸⁵ Furthermore, prolonged polyuria from any cause leads to partial resistance to the antidiuretic action of vasopressin (VP), caused by dilution of the renal medullary interstitium.⁸⁶ This can mean that patients with severe polyuria due to dipsogenic DI may appear to have partial NDI. The accuracy of the test can be enhanced by the incorporation of AVP measurement with a reliable radioimmunoassay, if available. We incorporate measurement of thirst by visual analogue scale, which gives valuable information in the diagnosis of specific thirst problems.

The most accurate diagnosis of HDI is attained by direct measurement of plasma AVP concentration during intravenous infusion of hypertonic saline86,87 (Fig. 14-7). Patients with HDI are identified by undetectable or subnormal plasma AVP concentrations with respect to plasma osmolalities, whereas patients with DDI and NDI have plasma AVP responses in the normal range. DDI and NDI can be distinguished by relating plasma AVP concentration to urine osmolality at the end of the test. NDI is characterized by inappropriately high plasma AVP values for concomitant urine osmolality, whereas DDI patients show an appropriate relation. A visual analogue scale⁵³ is equally useful in this form of osmotic stimulation.

Because the concentrations of AVP in urine are higher than those in plasma, and thus are detectable by a wider range of available assays, measurement of urinary AVP concentration during osmotic stress has been proposed as an additional alternative to the measurement of plasma AVP in the diagnosis of HDI, but this method needs further evaluation.⁸⁸

Once the diagnosis of HDI has been confirmed, imaging of the hypothalamic-pituitary region with MRI scanning is mandatory to exclude structural lesions. Sellar tumors in patients with HDI most often are craniopharyngiomas. A stalk mass has a wider differential diagnosis, including craniopharyngioma, germinoma, metastasis, lymphocytic hypophysitis, and stalk thickening in autoimmune HDI. Typical appearances may be found in sarcoid, hemochromatosis, and other inflammatory conditions. The posterior pituitary has as a characteristic bright signal on T1-weighted MRI, which is absent in most patients with HDI.⁸⁹ The posterior lobe signal is also diminished in the elderly and in patients with anorexia nervosa, septic shock, and poorly controlled diabetes mellitus, and those on hemodialysis. It is thought that this may represent persistent hypersecretion and thus decreased VP-NPII complex content.

If the diagnosis is thought to be idiopathic DI, awareness of the possibility of an autoimmune origin is important. Routine measurement of thyroid function, vitamin B₁₂, and autoantibodies is worthwhile, whereas tests for primary adrenal failure should be considered when clinically indicated. Serum angiotensin-converting enzyme concentration and chest films should be considered if sarcoid is suspected. It is important to repeat MRI imaging when initial films are normal, as some parasellar tumors such as germinomas can present with DI prior to the development of radiologic abnormalities. If stalk lesions are present, serum hCG and α-fetoprotein measurements may give a clue to the presence of germinoma, and early repeat MRI is important for assessing tumor growth. Biopsy should be considered early, as germinomas are best treated with chemotherapy and radiotherapy rather than surgical intervention. Dynamic tests of anterior pituitary function should be considered in cases in which structural pituitary lesions exist. Data in children suggest that growth hormone deficiency commonly accompanies autoimmune HDI,⁹⁰ although anecdotal evidence suggests that this is not the case in adults.

Patients with NDI should undergo renal investigations as appropriate, including urine microscopy and renal tract ultrasound to exclude obstruction, and tests of other aspects of tubular function. Genetic studies in suspected familial disease remain research tools.

Adipsic Diabetes Insipidus

Although diabetes insipidus is almost always associated with normal thirst and drinking appropriate to clinical needs, adipsic diabetes insipidus (ADI) is a rare but highly complex condition. It is seen most commonly after clipping of anterior communicating artery aneurysms, following subarachnoid hemorrhage91,92; the vascular supply to the osmoreceptors is derived from small arteries arising from the anterior communicating artery, and it is assumed that these vessels are damaged during aneurysm clipping, and that infarction of the circumventricular organs occurs where the osmoreceptors are sited. The osmoregulatory defect is almost always permanent, although anecdotal, unpublished reports have described recovery. Extensive hypothalamic surgery for craniopharyngioma,⁹² or, rarely, pituitary macroadenoma,⁹³ have been reported to cause ADI.

In ADI secondary to clipping of the anterior communicating artery, a pure osmoreceptor defect is present. Osmotic stimulation with hypertonic saline causes no rise in plasma AVP or in thirst ratings, despite marked hyperosmolality. In contrast, nonosmotic baroregulated AVP secretion is completely normal, with secretion of AVP to produce plasma concentrations a hundred-fold higher than those needed for maximal urine concentration.⁹⁴ The AVP synthesis/secretion unit of the SON/PVN/posterior pituitary is thus intact, but is not innervated by the osmoreceptors. In patients who undergo destructive surgery to the pituitary, all secretory function is lost.⁹⁴

The diagnosis of ADI presents a management dilemma.⁹⁵ Patients are unable to perceive changes in plasma tonicity via the usual thirst mechanisms and are vulnerable to marked swings in plasma sodium concentration. Severe hypernatremia is a particular hazard. Management requires regular desmopressin, fixed fluid intakes that may vary with climatic conditions, and regular review for measurement of plasma sodium. Recent data have also highlighted associated hypothalamic abnormalities that are often seen with ADI (Table 14-2), including hypothalamic obesity, seizure disorders, sleep apnea, and thermoregulatory disorders.⁹² Episodes of dehydration are often complicated by thrombotic complications, including pulmonary thromboembolism.^92,96 Many patients die prematurely owing to postsurgical complications, electrolyte abnormalities, or sleep apnea.

Treatment for Diabetes Insipidus

Although the intact thirst mechanism prevents dehydration in DI, the need to continually seek fluids and facilities for polyuria is a great inconvenience. The treatment of choice is DDAVP (desmopressin), a synthetic, long-acting VP analogue that possesses minimal pressor activity and has twice the antidiuretic potency of AVP. It can be administered as an intranasal spray, but more often is given orally in two to three daily doses. The main complication is dilutional hyponatremia, which can produce headaches, bloating, and occasionally seizures. Dilutional hyponatremia is minimized by omission of DDAVP once weekly, to allow a hypotonic diuresis that prevents water intoxication. Partial HDI (urine volume <4 L per 24 hours) can be managed with adequate fluids to quench thirst with a nocturnal dose of DDAVP to prevent loss of sleep due to nocturia. Plasma electrolytes should be measured at regular intervals after the introduction of treatment to look for hyponatremia; a decrease in plasma sodium concentration should prompt a therapy review.

NDI due to an acquired metabolic problem is best managed by addressing the underlying cause and maintaining adequate hydration while function recovers. For those patients with congenital NDI or in whom the acquired defect is irreversible, a number of additional measures including thiazide diuretics (hydrochlorothiazide, 25 mg/24 hours) may be used; prostaglandin inhibitors such as nonsteroidal antiinflammatory drugs (ibuprofen, 200 mg/24 hours) and dietary salt restriction also can be used. All work probably via a combination of reducing glomerular filtration rate and interfering with the diluting capacity of the distal nephron. Occasionally, DDAVP can produce some benefit.

As with other causes of DI, the approach to DDI should try to address the underlying cause. This may be difficult. Switching treatment to alternative agents may help those patients with chronic schizophrenia and a history of hyponatremia. Individuals with persistent DDI are at risk for hyponatremia if treated with DDAVP. Reduction in fluid intake is the only rational treatment.

Introduction

In 1956, in a presentation to the American Society for Clinical Investigation, Frederic Bartter and William Schwartz first described the syndrome of inappropriate antidiuretic hormone secretion (SIADH) as it occurred in two patients with lung carcinoma who had severe hyponatremia at presentation.⁹⁷ By alternating fluid restriction with fluid loading, the investigators demonstrated a state of antidiuresis and hypothesized that their patients manifested a clinical syndrome of inappropriate antidiuresis secondary to excess circulating antidiuretic hormone. Once radioimmunoassays for the measurement of plasma AVP became available, their index clinic description and pathophysiologic hypothesis were substantiated by papers that reported elevated plasma vasopressin concentrations in the syndrome,⁹⁸ which is now recognized to occur in a wide spectrum of disease states. However, differentiation of SIADH from other causes of hyponatremia remains important to the prescription of appropriate treatment regimens.

Causes of Siadh

SIADH is associated with a great number of illnesses and most often presents as a coincidental biochemical manifestation of the causative disease. The most common causes of SIADH are summarized in Table 14-3. The origin of SIADH is clinically divided into four categories: malignant, pulmonary, pharmacologic, and neurologic causes.

Bartter and Schwartz first described SIADH in association with bronchogenic lung carcinoma. In small cell carcinoma of the lung, SIADH is relatively common, occasionally occurring as the presenting abnormality that prompts a search for the tumor.⁹⁹ Most neoplasms have been reported to cause SIADH, and the association between malignant disease and SIADH is so strong that a patient presenting with SIADH, general malaise, and unexplained weight loss should be considered to have an underlying malignancy until proven otherwise.

SIADH is commonly associated with intracranial diseases, particularly traumatic brain injury,65–67 in which almost all cases resolve spontaneously with recovery from brain injury. More than 50% of patients with subarachnoid hemorrhage develop hyponatremia in the first week following the bleed, and 70% of these events are due to SIADH.¹⁰⁰ SIADH also commonly occurs after hypophysectomy and after surgery for primary brain tumor.

Many drugs are important clinical causes of hyponatremia. The selective serotonin reuptake inhibitors (SSRIs) are thought to cause SIADH by direct stimulation of AVP secretion by serotonin.¹⁰¹ SIADH usually occurs in the first few weeks after SSRIs are introduced, particularly in elderly patients.¹⁰² It has been estimated that 12% of hospitalized patients on SSRI therapy develop SIADH.¹⁰³ Psychotropic medications such as phenothiazines, haloperidol, and tricyclic antidepressants all cause SIADH. Many patients who have conditions treated with psychotropic drugs also have abnormal thirst; if these patients develop drug-induced SIADH, they can develop very significant hyponatremia. For instance, up to 20% of patients with chronic schizophrenia have psychogenic polydipsia, and excess fluid intake can precipitate severe hyponatremia. MDMA (“Ecstasy”) is thought to stimulate both AVP release and thirst as a result of hyperthermia, and this has been implicated in the development of cases of life-threatening hyponatremia.¹⁰⁴

SIADH must be distinguished from exercise-associated hyponatremia (EAH),¹⁰⁵ in which the electrolyte profile mimics SIADH. The pathophysiology is different, however. EAH occurs in athletes who ingest excessive hypotonic fluid during exercise, with resultant dilutional hyponatremia. Women, marathon runners racing for longer than 4 hours, and athletes of low body mass index are at greatest risk.¹⁰⁶ Although some athletes with EAH fail to suppress AVP, EAH probably should be considered to be distinct from SIADH.

Pathophysiology of Siadh

SIADH occurs by definition when AVP secretion is not suppressed when plasma sodium concentration falls below the osmotic threshold for SIADH. However, Zerbe and colleagues were able to differentiate four different types of SIADH, depending on the pattern of AVP secretion ⁹⁸ (Fig. 14-8).

Type A is the most common form of SIADH (40%). Characteristically, Type A patients exhibit excessive, random secretion of AVP, with loss of the close linear relationship between plasma osmolality and plasma AVP. Plasma AVP concentrations fluctuate widely in this variant, with no relationship to ambient plasma osmolality, but with consistent antidiuresis and inappropriate urine concentration despite hyponatremia. Type A is common in lung cancer; in vitro studies have demonstrated that some lung tumors synthesize AVP,¹⁰⁷ and tumor tissue stains positive for AVP messenger RNA.¹⁰⁸ However, Type A SIADH also occurs in non-neoplastic disease, for which ectopic AVP secretion could not be implicated. Plasma AVP concentrations in Type A SIADH are not suppressed by drinking,¹⁰⁹ which makes patients vulnerable to the development of severe hyponatremia.

Type B is also common (40%). The osmotic threshold for AVP release is lowered—a “reset osmostat”—in such a way that secretion of AVP occurs at lower plasma osmolalities than normal. At plasma osmolalities above this reset threshold, the linear relationship between plasma AVP and plasma osmolality is preserved. Equally, because AVP is suppressed at plasma osmolalities below the lower, reset threshold, overhydration leads to suppression of AVP release. A hypotonic diuresis then develops, which protects against the progression to severe hyponatremia. Similar lowering of the osmotic threshold occurs in hypovolemia and hypotension, leading to speculation that the function of afferent baroregulatory pathways is disturbed in these patients.

Type C is a rare condition characterized by failure to suppress AVP secretion at plasma osmolalities below the osmotic threshold. Plasma AVP concentrations are thus inappropriately high at low plasma osmolalities, but a normal relationship is noted between plasma osmolality and plasma AVP at physiologic plasma osmolalities. This variant may be due to dysfunction of inhibitory neurons in the hypothalamus, leading to persistent low-grade basal AVP secretion.

Type D provides a rare clinical picture of SIADH without detectable circulating AVP.¹¹⁰ It is postulated that a nephrogenic syndrome of inappropriate antidiuresis (NSIAD) may be responsible for the Type D picture of SIADH.¹¹¹ Recent reports described two male infants in whom gain-of-function mutations in the V2 receptor led to a clinical picture of SIADH, with undetectable AVP levels. Both children were diagnosed in infancy. Identified mutations had different nucleotide substitution with different levels of V2 receptor activation.¹¹¹

Studies in rat models of SIADH have demonstrated that the increase in water reabsorption is secondary to AVP-mediated expression of renal aquaporin-2,¹¹² with a consequent increase in AQP protein excretion in the urine.¹¹³ Aquaporin-2 recruitment has been shown to be reversible through administration of a V2 receptor antagonist^112,114 that provides the scientific rationale for the use of AVP antagonists in the treatment of this condition. Prolonged SIADH is associated with “escape” from antidiuresis, with downregulation of AQP2 mRNA and protein expression.

Although patients with SIADH have ambient plasma osmolalities that are below the physiologic osmotic threshold for thirst, they continue to drink apparently normal fluid volumes. In experiments in which patients with SIADH of mixed causes were infused intravenously with hypertonic sodium chloride solution, the osmotic threshold for thirst was lowered to a setting that was identical to that for AVP.¹⁰⁹ Parallel lowering of the thresholds for thirst and AVP release ensured the maintenance of fluid intake, predisposing to persistent hyponatremia.

As fluid intake is maintained in the face of reduced free water clearance, patients with SIADH can develop severe hyponatremia. However, hyponatremia is often limited by “escape from antidiuresis.” This protective homeostatic mechanism occurs when the kidney begins to increase free water clearance despite inappropriate plasma AVP concentrations.¹¹⁵ Initial natriuresis is followed by an increase in urine flow¹¹⁶ with consequent water loss; this allows plasma sodium to stabilize and, occasionally, to rise. Although plasma sodium concentration does not usually rise into the normal physiologic range during escape from antidiuresis, the development of severe hyponatremia is prevented.

Experimental models of SIADH, in which hyponatremia was induced in Sprague-Dawley rats by the injection of subcutaneous desmopressin, showed that desmopressin administration alone did not lead to hyponatremia.¹¹⁷ Plasma volume expansion due to water loading, leading to increased renal perfusion pressure, was vital for initiation of escape from antidiuresis.¹¹⁸ A decrease in AQP2 protein expression and V2 receptor binding capacity^119,120 has been postulated to cause the renal resistance to AVP observed during escape from antidiuresis.

In normal physiology, AVP has long-term effects on AQP2 via mRNA and protein expression, but it has short-term effects via the V2 receptor, leading to increased cyclic adenosine monophosphate (cAMP). It is likely that this short-term AVP action is also altered in escape, because reduced levels of cAMP in the collecting ducts of “escaped” rats have been demonstrated.¹²¹ This finding of reduced cAMP activity suggests both the short-term regulation of AQP activity by reduced vesicle “shuttling” and the long-term downregulation of AQP mRNA expression in the genesis of “escape from antidiuresis.”

Diagnosis of Siadh

Essential criteria for the diagnosis of SIADH are presented in Table 14-4. Two additional supplemental criteria—raised plasma vasopressin concentration and abnormal water load test—are rarely used in clinical practice. Water loading of a patient with SIADH runs the risk of symptomatic hyponatremia; therefore, this procedure should be restricted to centers with considerable experience in managing disorders of water balance. Plasma AVP concentrations are elevated in almost all causes of hyponatremia and therefore are rarely of diagnostic benefit in hyponatremic patients; lack of access to local radioimmunoassays dictates that the results of tests may take weeks to come back, which further diminishes their clinical value.

The minimum data set for the diagnosis of SIADH is hyponatremia in a euvolemic patient with inappropriate concentrated urine (osmolality >100 mOsm/kg), elevated urine sodium (>30 mmol/L), and exclusion of cortisol and thyroid hormone insufficiency. Older textbooks dictate that urine osmolality should exceed plasma osmolality for the diagnosis to be secure, but osmoregulatory physiology indicates that this criterion is redundant. If plasma osmolality is below the osmotic threshold for AVP secretion, plasma AVP levels should be suppressed, allowing hypotonic diuresis with urine osmolality <100 mOsm/kg. Urine osmolalities in excess of 100 mOsm/kg indicate inappropriate urine concentration and are compatible with the diagnosis of SIADH. Many hyponatremic patients do not undergo the requisite tests and may be misdiagnosed with SIADH without satisfying the diagnostic criteria.

Differential Diagnosis of Siadh

Treatment for Siadh

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