Osmoregulation in clinical disorders of thirst appreciation
1998; Wiley; Volume: 49; Issue: 2 Linguagem: Inglês
10.1046/j.1365-2265.1998.00572.x
ISSN1365-2265
AutoresKieran McKenna, Christopher J. Thompson,
Tópico(s)Ion Transport and Channel Regulation
ResumoNormal human cellular function depends on constant tonicity of the extracellular fluid. As water is constantly lost from the kidneys, lungs, skin and alimentary tract, even in conditions of antidiuresis, there is a need to replace fluid deficits by the maintenance of adequate water intake. In healthy man, water homeostasis is so accurately controlled that plasma osmolality is precisely maintained within a remarkably narrow range of 282–298 mOsm/kg. This exquisite control is achieved by the close integration of the antidiuretic action of vasopressin (AVP), which regulates water excretion, and the sensation of thirst, which governs water intake. Disturbances of the secretion or function of vasopressin, or of the regulation of thirst appreciation and drinking behaviour, can cause profound clinical abnormalities in sodium and water homeostasis. Since the development of sensitive radioimmunoassays for the measurement of vasopressin in plasma, the physiological characteristics of AVP release have been established, and abnormalities of control of AVP secretion and function in diseases of water homeostasis, such as diabetes insipidus and the syndrome of inappropriate antidiuresis (SIADH), have been well defined. Because the definition of the thirst has been the topic of some controversy, and because the measurement of the sensation of thirst has been regarded as subjective and inaccurate, clinical disorders characterized by abnormal thirst have received comparatively little research attention. In recent years however, the development of accurate, methods for the measurement of thirst has improved our understanding of the physiology of thirst and advanced our knowledge of how abnormalities of thirst appreciation can contribute to clinical disorders of water balance. In this review, the physiology of control of water intake will be summarized and the pathophysiology and clinical features of clinical disorders of thirst appreciation will be described. The physiology of osmoregulation has previously been reviewed in depth (6) but we shall give a brief introductory overview. Plasma osmolality is the most important physiological determinant of vasopressin secretion. Changes in plasma osmolality are detected by specialised magnocellular neurones which animal data locate in the circumventricular organs (10; 50; 85) in the anterior hypothalamus, where it is thought that fenestrations in the blood brain barrier allow access of plasma solutes to osmosensitive neural tissue (89). The identification of water channels, or aquaporins, in brain tissue (aquaporin 4) has challenged this traditional theory. Rnase protection studies with aquaporin 4 probes indicated that the brain was the principal site of expression, prompting speculation that aquaporins in cell membranes may be the mechanism by which osmoreceptor neurones obtain their information about extracellular tonicity (1). Furthermore, as in situ hybridization studies identified particularly strong signals from the paraventricular and supraoptic nuclei, which synthesize AVP (48), the concentration of water channels in these nuclei may indicate that they have osmoreceptor properties independent of those of the circumventricular organs (37; 13). Further research is required to define the role of aquaporins in osmoregulation, but their identification in the brain is extremely exciting. Within the circumventricular organs, the subfornical organ (SFO) and the organum vasculosum laminae terminalis (OVLT) are the sites of the vasopressin osmoreceptors. Animal studies suggest that the osmoreceptors which control thirst are sited in the AV3V region, anatomically discrete from the site of the vasopressin osmoreceptors (91). Data from a human case report of defective osmoregulation of thirst, with preservation of osmoregulated vasopressin release, (31) would provide corroborative clinical evidence for the existence of separate osmoreceptors for thirst and vasopressin release. Neural signals from the osmoreceptors are transmitted to the supraoptic and paraventricular nuclei, where vasopressin is synthesized, and from where neurones terminate in the posterior pituitary, the site of AVP release into the circulation. It is thought that similar neural impulses from the osmoreceptors governing thirst sensation terminate in the cerebral cortex where they initiate drinking, but the neuroanatomy is less well understood. Electrolytic ablation of the ventral portion of the nucleus medianus has been reported to produce both adipsia and hyperdipsia in the rat, however (22, b) which suggests that the nucleus medianus controls the passage of signals from the circumventricular organs to the cerebral cortex. Elevations in plasma osmolality therefore produce increases in plasma vasopressin concentrations, as shown in Figure 1. Regression analysis reveals the physiological relationship between plasma osmolality and plasma vasopressin to be linear and to be described by the equation pAVP = 0.43 (pOsm − 284.3), r = + 0.92, P < 0.001, where vasopressin is expressed as pmol/l (80). The slope of this line reflects the sensitivity of the osmoregulatory unit. The abscissal intercept of the line, at a mean of 284.3 mOsm/kg in healthy man, represents the ‘osmotic threshold’, at which secretion of vasopressin into the plasma begins. Although sensitive cytochemical assays can detect minute quantities of circulating vasopressin at osmolalities below 284.3 mOsm/kg (8), these low concentrations of vasopressin have little antidiuretic effect, as a hypotonic diuresis develops when plasma osmolality is lowered below this ‘set point’. The concept of an osmotic threshold for vasopressin release is therefore biologically sound. The third characteristic of this equation is the close relationship between plasma osmolality and plasma vasopressin, as indicated by the correlation coefficient relating the two variables. There are wide inter-individual variations in the relationship between plasma vasopressin and plasma osmolality, but the relationship is very reproducible within an individual, on repeated testing (82). Results of measurement of (a) plasma vasopressin (pAVP) and (b) thirst in response to hypertonic saline infusion in ten healthy volunteers. - - - assay limit of detection for vasopressin (0.3 pmol/l). —- regression lines described in text. The close relationship between plasma osmolality and plasma vasopressin is lost during the act of drinking, which causes rapid suppression of vasopressin secretion, before changes in plasma osmolality occur (24; 77; Figure 2). The fall in plasma vasopressin concentrations is almost instantaneous and approximates closely to the plasma half-life of the hormone (77), suggesting that the act of swallowing itself may switch off vasopressin secretion. It has been proposed that the mechanism which inhibits vasopressin secretion during swallowing is the activation of oropharyngeal stretch receptors which send inhibitory signals to the hypothalamus via an, as yet unidentified, neural pathway (66). (a) Plasma osmolality, (b) vasopressin and (c) thirst responses to hypertonic saline infusion, followed by drinking (○) or water deprivation (•) in healthy controls. Adapted from 77) with permission. The sensation of thirst is subjective and not easily quantifiable by scientific measurement. 62) defines thirst as ‘a conscious sensation of a need for water and a desire to drink’, and according to this analysis has measured the osmotic threshold for the onset of thirst to be around 294 mOsm/kg (58), which is approximately 10 mOsm/kg above the osmotic threshold for vasopressin release. However, this analysis suggests that thirst rarely occurs in situations where plasma osmolality lies within the normal physiological range. This is contrary to clinical experience and suggests that osmoregulated thirst plays no role in governing fluid intake in physiological situations. The development of simple visual analogue scales for the measurement of thirst has led to this traditional definition of thirst being challenged. Most visual analogue scales are uncalibrated, 10 cm long lines, upon which subjects are invited to place a cross between two extremes—for instance ‘not thirsty at all’ and ‘extremely thirsty’. As there is close concordance between the responses to questions covering a range of sensations, including ‘how thirsty are you?’, ‘how much do you desire water?’ and ‘how dry is your mouth?’, the first question is most commonly used. A number of groups have employed this simple technique to measure thirst and have shown in carefully conducted experiments that thirst appreciation does change within the physiological range of plasma osmolalities (63; ; 75) and that thirst ratings so obtained correlate closely with ambient plasma osmolality. Thirst responses defined by this method are highly reproducible within an individual (82) and correlate well with the subsequent volume of water drunk (75). Using a visual analogue scale, we have shown that the osmotic threshold for the onset of thirst is actually lower than that identified by Robertson and which is very similar to that for vasopressin release (Thompson wt al., 1986, Fig. 1). Calculation of a linear regression equation from the data shows that the relationship between pOsm and thirst is just as sensitive as that between plasma osmolality and plasma vasopressin. The osmotic threshold for thirst onset and the close relationship between plasma osmolality and thirst are highly reproducible within individuals on repeated testing (82). These data propose an alternative model of thirst appreciation, whereby thirst occurs when plasma osmolality rises above an osmotic threshold which is similar to that for vasopressin release, and the intensity of thirst varies according to the ambient plasma osmolality. In other words, within the physiological range of plasma osmolalities, thirst sensation is mild and initiates fluid intake sufficient to replace insensible water loss, whereas the more intense thirst generated by higher plasma osmolalities prompts the larger fluid intake required to replenish more severe fluid balance deficits. The non-osmotic switch-off of thirst during the act of drinking is also very similar to that of vasopressin (Fig. 2), with a rapid fall in thirst ratings before significant changes in plasma osmolality occur (77; 66), suggesting again that pharyngeal distension causes activation of neural inputs to the hypothalamus causing immediate suppression of thirst appreciation. This is clearly a sophisticated defence mechanism which protects against over-hydration. As there is a delay in gastrointestinal absorption of water, if drinking stopped only when plasma osmolality returned to normal, there would always be a significant residual volume of fluid in the stomach or duodenum, which when absorbed would lower plasma osmolality and require a compensatory diuresis to restore water balance. The osmoreceptors for thirst are solute specific. Acute elevation of blood glucose is not dipsogenic in either healthy volunteers (90) or patients with IDDM (79) while urea has only weak dipsogenic properties (90). Thirst may also be stimulated by hypotension or hypovolaemia (56), although the mechanisms involved are not well understood. There are conflicting data regarding the effects of atrial natriuretic peptide (ANP) on thirst. There is evidence that ANP reduces thirst during hypertonic saline infusion (12), but more recent data failed to show any effect of ANP, even at high plasma concentrations, on either thirst or vasopressin secretion (88). Thirst is the most prominent symptom of cranial diabetes insipidus (CDI) and the stimulus to the increased fluid intake which is necessary to replace urinary losses (5). In the absence of a normal thirst mechanism, patients with CDI would rapidly dehydrate due to failure to appreciate rising plasma tonicity and to respond by increasing fluid intake. The regulation of thirst is normal in the vast majority of patients with cranial diabetes insipidus (76). Regression analysis of the relationship between thirst and plasma osmolality shows that the osmotic threshold for onset of thirst is similar to that of controls, and that there is a similar close correlation between thirst ratings and ambient plasma osmolality (76). The intact thirst mechanism in CDI allows patients to survive and maintain near normal plasma osmolality, even without treatment. The Brattleboro rat has cranial diabetes insipidus as a result of a genetic defect in vasopressin synthesis. Studies in this animal model have shown that the renin-angiotensin system is more responsive to renin-dependent thirst challenges than control rats (21). The authors proposed that thirst in diabetes insipidus may in part be due to a renin-angiotensin system which has been activated by volume-depletion secondary to polyuria. Vasopressin replacement abolishes thirst, but not hyper-reninaemia, in the Brattleboro rat, however (29) which would argue against an important role for renin in the generation of thirst in diabetes insipidus. Patients with diabetes insipidus are also hyper-reninaemic in comparison to healthy controls, possibly due to blood volume contraction (2), but there have been no convincing studies of renin-dependent thirst in human diabetes insipidus. On present evidence, the thirst in diabetes insipidus seems to be an appropriate physiological response to elevation of plasma osmolality. Compulsive water drinking has been described in association with CDI (39; 76). In clinical practice, the rare patient with the combination of pathological thirst and vasopressin deficiency may be difficult to distinguish from patients with primary polydipsia. One clinical clue to the diagnosis of diabetes insipidus with pathological thirst is that, in contrast to patients with primary polydipsia, symptoms of polyuria and thirst persist throughout the night, whereas they often disappear in primary polydipsia. The diagnosis of primary polydipsia in CDI patients depends upon the demonstration of absent AVP response to rising plasma osmolality during water deprivation test or hypertonic saline infusion. Management with desmopressin abolishes polyuria, but is potentially dangerous, as lowering of plasma osmolality does not abolish thirst. Continued drinking in the presence of desmopressin-induced antidiuresis may lead to the development of significant hyponatraemia. If a patient is unable to control the compulsion to drink, it is safer to withhold desmopressin therapy, even though this increases the risk of hypernatraemia if the patient is too unwell to drink due to intercurrent illness. The combination of diabetes insipidus and hypodipsia has been described in association with surgery to anterior communicating artery aneurysms (58; 43; 49), head injury (76) and toluene exposure (74); a full list is given in Table 1. In contrast to essential hypernatraemia (see adipsic disorders), patients are characterized by partial or complete lack of thirst appreciation, despite polyuria due to vasopressin deficiency. Most detailed case studies have demonstrated complete adipsia and vasopressin deficiency in response to osmotic stimulation, but entirely normal AVP responses to non-osmotic stimuli such as hypotension and apomorphine (58; 49; 74, Fig. 3), which suggests that the site of the lesion is the osmoreceptor. Management of this condition is dealt with in the section on adipsic disorders. Plasma vasopressin responses to hypertonic saline infusion (a) and trimetaphan-induced hypotension (b) in a patient with adipsic diabetes insipidus. Shaded areas represent normal range in healthy individuals. Adapted from 74), with permission. Thirst is a common symptom of metabolic decompensation in diabetes mellitus, and represents a physiological response to glycosuric diuresis. The characteristics of osmoregulated thirst and AVP release have been shown in careful studies to be entirely normal in Type 1 diabetes mellitus (79, 1989). Interestingly, acute hyperglycaemia is not dipsogenic in Type 1 diabetes (79) which suggests that thirst in poorly controlled diabetes is related to volume depletion secondary to polyuria, rather than the osmotic effects of hyperglycaemia. Osmoregulation is also entirely normal in Type 2 diabetes, though recent data has shown that survivors of hyperosmolar coma (HONK) respond to the hypernatremia of water deprivation with attenuated thirst and drinking (84). The attenuated thirst and drinking responses may be an important factor in the development of the hypernatraemic dehydration which is characteristic of this condition. Primary polydipsia is a complicated spectrum of diseases in which a primary abnormality of thirst causes excessive drinking and polyuria. There have been several syndromes which have been identified to have been associated with primary polydipsia and these are listed in Table 2. Polydipsia which is not associated with underlying illness is sometimes referred to as compulsive water drinking. First described by 4), it was defined as an excessive consumption of fluid due to psychological disturbance. Most of the patients in the original series suffered from conversion hysteria or hypochondriasis, though one patient had no identifiable psychological abnormality. Compulsive water drinking is sometimes termed dipsogenic diabetes insipidus, first used by 59) which more accurately describes the clinical abnormalities associated with the condition. The syndrome is characterized by excessive water intake, for which the patient offers the explanation of severe, persistent, unquenchable thirst and which leads to the production of hypotonic polyuria. Clinical examination is unremarkable and the only laboratory abnormalities are mild reduction in plasma osmolality and plasma sodium concentrations. The hyperintense signal which is seen on high energy T1 weighted nuclear magnetic resonance imaging of the neurohypophysis in healthy humans, but is absent in some patients with idiopathic cranial diabetes insipidus, is clearly visible in patients with this syndrome (47). Most patients with primary polydipsia have been found to have normal osmoregulation of vasopressin (7; 83), though some workers have reported impaired osmotically stimulated AVP release, which they suggested could represent downregulation of AVP release due to chronic overhydration (46). It has been argued that attenuated vasopressin responses to dehydration may explain the impairment in urinary concentrating ability which is well recognised in primary polydipsia (4). We would suggest that it is more likely that the chronic polyuria causes impaired renal sensitivity to vasopressin, as patients do not always concentrate urine appropriately despite normal AVP responses to water deprivation, and urine osmolality does not rise appropriately after administration of desmopressin. Three distinct abnormalities of the control of thirst appreciation have been identified in clinical studies. First, the osmotic threshold for thirst appreciation is lowered such that patients feel thirsty even at plasma osmolalities associated with complete abolition of vasopressin secretion (61; 82). The continued fluid intake at low plasma osmolalities ensures that vasopressin secretion is completely suppressed, with the development of the hypotonic diuresis characteristic of the syndrome. Because plasma vasopressin is undetectable, it can be difficult to differentiate primary polydipsia from cranial diabetes insipidus, though basal plasma osmolality tends to be low in primary polydipsia and high normal in diabetes insipidus; dynamic tests of vasopressin secretion, such as water deprivation tests or hypertonic saline infusion are mandatory for the differentiation of the two syndromes. The second abnormality of thirst in primary polydipsia is that patients drink more than healthy controls in response to a given rise in plasma osmolality, and finally, they do not suppress thirst during drinking, and continue to feel thirsty even when imbibing large volumes of water (83). It has been suggested that primary polydipsia is caused by abnormal function of the osmoreceptors governing thirst (61), but the failure of drinking to suppress thirst indicates that non-osmotic control of thirst is also abnormal. It seems more likely that there is a central abnormality in the integration of osmotic and non-osmotic control of thirst in primary polydipsia. The association between polydipsia and schizophrenia has been recognised for some time (67). Approximately 20% of patients with chronic schizophrenia have polydipsia (15). This often results from an increased desire for water independent of thirst, and sometimes represents an irrational belief in the therapeutic benefits of drinking large volumes of water. Up to 4% of schizophrenic patients develop hyponatraemia, and water intoxication may occur, which can progress to impairment of cognitive function, fits, permanent neurological deficits and even death (57; 73). Hyponatraemia occurs particularly if patients are treated with drugs which reduce free water clearance (35), particularly carbamazepine and phenothiazines. Complex abnormalities of osmoregulation have been described in psychotic patients with polydipsia. Exaggerated AVP responses to osmotic stimulation have been reported in comparison to non-polydipsic schizophrenic patients, with normal suppression of AVP levels after drinking (26, 1996a). The osmotic threshold for thirst is lowered below that for AVP release, however, so that patients drink so as to suppress plasma osmolality to levels associated with constant suppression of AVP, and therefore permanent hypotonic diuresis develops. Polydipsia alone is very unlikely to cause the hyponatraemia which occurs in a significant minority of patients, however, as the normal human kidney is capable of excreting up to 20 litres of water daily. Individual patients have been reported to have inappropriate secretion of vasopressin, particularly in association with phenothiazine agents, and there have also been reports of a lowering of the osmostat for vasopressin release (54; 26), either of which could cause hyponatraemia. Oropharyngeal suppression of drinking is short lived in polyuric schizophrenics (28), such that they begin to feel thirsty inappropriately soon after drinking, and continue to drink despite have ingested sufficient fluid to satisfy physiological requirements. The pathophysiology of the abnormal thirst in schizophrenic patients is unknown, but is likely, given the reported abnormalities in both osmotic and non-osmotic regulation, to be a defect in the central integration of thirst in the higher centres, rather than a lesion in the osmoreceptors. Excessive thirst and drinking have also been reported in some patients with intracerebral tumours, most frequently craniopharyngiomas. Polydipsia is particularly common after cranial surgery for large craniopharyngiomas, and is often associated with polyphagia, presumably due to hypothalamic damage. Polydipsia in association with normal osmoregulation of AVP has been reported in a patient in whom hypothalamic sarcoidosis was spectulated to have caused the excessive thirst (7), and also in association with enhanced AVP release in a patient with autopsy-proven hypothalamic sarcoid (38). In one study of 11 patients with documented sarcoidosis and proven or suspected hypopituitarism, a range of abnormalities of osmoregulation were identified, with two patients having CDI, one patient CDI and adipsia, one patient adipsia alone and three patients having excessive thirst (71). The data indicated that disorders of thirst are more common than AVP deficiency in patients with hypothalamic sarcoidosis, and should be actively sought in this patient group. The basis of management of primary polydipsia lies in the treatment of any underlying disorder. Recent reports have suggested that clozapine can diminish abnormal thirst and correct the tendency to hyponatraemia in this patient group (33; 69). It is not clear however, whether the successful abolition of osmoregulatory abnormalities is due to the neurotransmitter effects of clozapine, or to the effective treatment of the underlying psychiatric disorder. Treatment of cerebral sarcoid with corticosteroids may abolish polydipsia. Management of primary polydipsia is difficult. Desmopressin therapy is contraindicated, as lowering plasma of osmolality does not abolish thirst and there is a significant risk of the development of water intoxication and severe hyponatraemia. An explanation of the diagnosis usually satisfies the patient, but rarely produces the behavioural changes which are necessary in order to abolish the drinking disorder. There are few deleterious effects associated with the syndrome, though hyponatraemia can occasionally develop, if, for instance, vasopressin is secreted in response to non-osmotic stimuli such as nausea or hypotension. Adipsic disorders are characterised by inappropriate lack of thirst, with consequent failure to drink in order to correct hyperosmolality. Plasma osmolality and plasma sodium are elevated and blood volume is contracted, with a raised blood urea. Despite markedly hyperosmolar plasma and hypovolaemia, patients deny thirst and make no efforts to drink. Mild hypernatraemia is often remarkably well tolerated, but poor cerebration and drowsiness are common symptoms and the condition can progress to somnolence, fits, hemiplegia, coma, rhabdomyolysis and acute renal failure. Patients do not increase fluid intake during acute illness such as gastroenteritis or pneumonia, with consequent rapid development of life-threatening hypernatraemia. Disorders characterised by adipsia or hypodipsia are uncommon, but a sufficiently large number have now been described in the literature for several distinct patterns of abnormal osmoregulation of thirst and vasopressin release to be recognised. Figure 4 is a schematic representation of the four main patterns of abnormal osmoregulatory function that have been described. Plasma vasopressin (pVP) and thirst responses to elevation in plasma osmolality (pOs) in four categories of adipsia. (a) (b) (c) (d) Reproduced from 6), with permission. Shaded areas represent normal range of responses. This is characterised by an upward resetting of the osmotic thresholds for both thirst and vasopressin release. Patients do not become thirst, or secrete AVP until their plasma osmolality has risen to their osmotic threshold, which is often over 300 mOsm/kg, has been reached, whereupon they osmoregulate and concentrate urine in order to protect their elevated osmoregulatory set point (16). If patients are water loaded they suppress thirst and AVP secretion, and develop a hypotonic diuresis. The combination of hyperosmolality and dilute urine can lead to the misdiagnosis of cranial diabetes insipidus, particularly if thirst is not formally assessed. This rare condition is sometimes referred to as essential hypernatraemia (25; 78). Computerised tomography and nuclear magnetic resonance scans of the hypothalamo-pituitary region are normal and the aetiology is uncertain. Patients are protected from extremes of hypernatraemia by their ability to perceive thirst and concentrate urine around their elevated set points, and so the only abnormality is chronic, mild hypernatraemia. Patients will usually respond to advice to drink around 2 litres of fluid daily, though this figure needs to be modified on a seasonal basis in areas of climatic fluctuation. This is characterised by subnormal thirst and vasopressin responses to osmotic stimuli, as shown by the decreased sensitivity or slope of the osmoregulatory lines for thirst and vasopressin release (Fig. 4). The ability to secrete some AVP has led to the suggestion that Type B adipsia is due to partial destruction of the osmoreceptors (60). 87), however, has argued that as magnocellular neurones have osmosensitive properties of (41), they are able to detect hyperosmolality and respond by releasing vasopressin, even if the osmoreceptors themselves are not functioning. Type B adipsia has been described in association with microcephaly and dysplasia of the corpus callosum (65), early puberty and aggressive behaviour (17) and increased renal sensitivity to vasopressin (18). Patients usually have intact baroregulated AVP release (17; 30), and normal vasopressin release in response to insulin-induced hypoglycaemia (17), and emesis (65), which places the site of the lesion at the osmoreceptor. The secretion of small amounts of AVP in response to osmotic stimulation and the increased renal sensitivity to the antidiuretic actions of AVP explains why some of these patients retain the ability to concentrate urine and limit free water excretion (16). The ability to drink to a certain extent and secrete small amounts of vasopressin in response to rising plasma osmolality protects from extreme hypernatraemia. Patients with Type B adipsia are also able to maximally dilute urine during water loading (65; 17), and do not develop episodic hyponatraemia if they do overhydrate. As with Type A, treatment depends on a fixed fluid intake of around 2 litres per day with adjustments for climatic variations, together with advice to see urgent medical attention in the face of acute illness, particularly diarrhoea. Complete destruction of the osmoreceptor is classified as Type C osmoreceptor dysfunction. Patients have complete absence of vasopressin release in response to rising plasma osmolality, and therefore present as adipsic diabetes insipidus, with lack of thirst despite marked polyuria. Surgery to ruptured aneurysms of the anterior communicating artery of the circle of Willis has been well documented to produce this syndrome (60; 43; 49; 3). Hypernatraemia, occurs in the peri-operative period in approximately 3% of operations on aneurysms of the anterior communicating artery and can be severe (43). The blood supply to the OVLT, the putative site of the osmoreceptor (55) is derived from perforating branches of the anterior cerebral and anterior communicating arteries (51) and it is assumed that these arterioles are damaged at the time of surgery. Other causes of complete osmoreceptor ablation include tumours, granulomata and toluene exposure (74). That the site of the lesion in Type C adipsia is the osmoreceptor, rather than the magnocellular neurones which synthesize and secrete vasopressin, is confirmed by the ability of these patients to secrete normal amounts of AVP in response to non-osmotic stimuli (Fig. 5). It is clear from published data that patients with Type C adipsia can produce plasma concentrations of vasopressin many times greater than those required to effect maximal urinary concentration in response to trimetaphan-induced hypotension (74; 3) or nausea (49). Interestingly, some of the patients that we have studied have also volunteered that they experienced thirst when mean arterial blood pressure was lowered by approximately 25% by the intravenous infusion of the ganglion-blocking agent trimetaphan, possibly due to the activation of volume receptors (86). Plasma vasopressin (pAVP) responses to trimetaphan-induced hypotension in patients with cranial diabetes insipidus with intact thirst mechanisms (•) and adipsia (○). Shaded area represent normal range of responses; - - - Limit of detection of AVP assay (0.3 pmol/l). One unusual aspect of complete osmoreceptor destruction is the inability of some patients to suppress AVP secretion. This manifests as the persistence in plasma of small quantities of AVP, measurable by radioimmunoassay, during oral water loading (3). The measurable AVP is biologically active as maximal free water clearance is not attained, (49) and patients are at risk of hyponatraemia if large volumes of fluids are inadvertently imbibed (60). Type C adipsia is the most difficult adipsic disorder to manage. Because thirst and vasopressin deficiencies are complete the patients are at great risk of life-threatening hypernatraemia. In particular, some patients who develop adipsic diabetes insipidus following surgery to aneurysms of the anterior communicating artery have significant defects of cognitive function, including short term memory loss, and are unable to manage their fluid intake without assistance. Desmopressin therapy is necessary to treat the diabetes insipidus and patients must be trained to drink approximately 2 litres of fluid daily. Patients need regular review and most authorities recommend daily weighing at home to detect changes in fluid balance status (60; 6), though poor patient compliance occasionally limits the effectiveness of this strategy. Chlorpropramide has been reported to improve thirst sensation in patients with adipsic diabetes insipidus (11) and cloifibrate has also been found to be useful (62) but we have found them to be of little value in our practice. Behaviour modification techniques have been used with modest success in some patients (36). The mainstay of management remains a regular schedule of water intake based on daily weights, urine output and frequent monitoring of plasma osmolality. This extremely rare form of osmoregulatory dysfunction manifests as adipsia with intact osmoregulated AVP release, and has been reported in a single case of a five year old child with optic atrophy, developmental delay and intracranial calcification (31). The incidence of hypernatraemia increases with advancing age, particularly in hospitalized individuals and those in long-stay institutions. In hospitalized patients over the age of 60 years, 1% have a serum sodium >146 mmol/l (68), which is associated with depressed sensorium and increased morbidity and mortality. In elderly residents of long-stay institutions, there is a high incidence of hypernatraemia and in a one year prospective study, 18% became hypernatraemic at some time during follow-up (44). During acute illness, the incidence of hypernatraemia rises, with 34% of nursing home patients developing a serum >150 mmol/l at the time of hospitalization for acute illness (40). Vasopressin deficiency does not seem to be the cause of the hypernatraemia. Immunocytochemical studies of the human hypothalamo-hypophyseal axis have shown an increase in the size of the supra-optic and paraventricular nuclei after the age of 60 years (20), and enlargement of the nuclei of the magnocellular neurones which synthesize vasopressin (34). These observations lend support to those clinical studies which have shown exaggerated AVP responses to hypertonic saline infusion (32) and water deprivation ( ) in healthy elderly men compared with younger men. However, some workers have found no age differences in AVP responses to hypertonic saline infusion (14), and lower AVP concentrations in elderly subjects following water deprivation have also been reported (42). In contrast to the increased osmotic secretion of AVP in the elderly, baroregulated AVP secretion has been reported to be decreased (64). Interestingly, drinking does not seem to activate the oropharyngeal inhibition of AVP secretion in elderly patients (53), and the failure to suppress AVP with resultant reduction in free water clearance (19) predisposes to hyponatraemia. Failure to suppress AVP secretion may have been important in the 11% of patients admitted to an acute geriatric unit who were found to have a plasma sodium of <130 mmol/l (72). There are therefore a complex series of abnormalities in the regulation of AVP secretion in the elderly. In contrast, the abnormalities in regulation of thirst are more straightforward. Thirst and drinking responses are attenuated in elderly patients in response to either water deprivation ( ) or hypertonic saline infusion (32; 14). One recent small study did suggest that thirst responses to hypertonic saline infusion were normal (70), but the remaining available data has uniformly found relative hypodipsia in older subjects. This attenuated thirst is compensated for during normal daily activities by the increased or normal vasopressin secretion, but if insensible water losses are increased by intercurrent illness, the failure to ingest appropriate amounts of water may well explain the increased incidence of hypernatraemia in elderly acute admissions. The reason for the decline in thirst appreciation with increasing age is not known. Hypodipsia may simply reflect global decline in neurological function, as for instance in the syndrome of multi-system atrophy (9) or represent a manifestation of cerebral cortical dysfunction (45). Alternatively, hypodipsia may be due to a decline in osmoreceptor function. In contrast to the global age-related abnormalities of regulation of vasopressin secretion, only osmotically-stimulated thirst has been reported to be abnormal in elderly patients; oropharyngeal inhibition of thirst is preserved (53). Although advancing age is not classified as a disorder of thirst, the relative hypodipsia which is commonplace significantly contributes to the morbidity of acute illness in this age group. Careful attention should therefore be paid to fluid and electrolyte balance, particularly in elderly residents of long-stay institutions and those with acute medical emergency conditions. The syndrome of inappropriate antidiuresis (SIADH) is characterized by hyponatraemic hypo-osmolality, with inappropriate elevation in plasma AVP and inappropriate urinary concentration. Patients are by definition euvolaemic, and, as plasma osmolality is suppressed to below the osmotic threshold for thirst, the desire to drink should be abolished and drinking should be minimal. In practice, patients with SIADH have fluid balance charts which closely resemble those of healthy individuals and do not show evidence of suppression of thirst. There is no published data on the regulation of thirst in SIADH, though four distinct patterns of abnormal AVP secretion have been described (60). We have studied two patients with SIADH due to small-cell tumours of the lung during hypertonic saline infusion; in these patients there was preservation of the close relationship between plasma osmolality and thirst ratings, but regression analysis revealed that the osmoregulatory line for thirst was re-set to the left, with a lowered osmotic threshold for thirst (Fig. 6). This would indicate that in SIADH, the threshold for thirst is re-set to ‘protect’ the lower ambient plasma osmolality. The mechanism for this is not clear and requires further study. (a) Plasma vasopressin (pAVP) and (b) thirst responses to hypertonic saline infusion in two patients with SIADH. Shaded areas represent the normal ranges in healthy individuals. Thirst and drinking are essential components of normal osmoregulation in healthy man. Abnormalities of thirst appreciation, in particular hypodipsia, have profound implications for water homeostasis. The combination of cranial diabetes insipidus and hypodipsia can have particularly serious consequences, with the potential for life-threatening hyponatraemia. Although the tools for measuring thirst are subjective and lack true specificity, their use in clinical research has contributed greatly to our understanding of the physiology of thirst appreciation and the abnormal control of thirst in osmoregulatory disorders. The precise neural control of thirst appreciation remains unknown, and perhaps as a result of this, satisfactory therapies for the treatment of disorders of thirst have not yet been developed; behavioural modification and re-training of drinking habits remain the rather limited cornerstones of management. The research by the authors which is noted in this article was supported by grants from the Medical Research Council, and by close collaboration with Professor Peter Baylis.
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