RECURRENT PREGNANCY-INDUCED POLYURIA AND THIRST DUE TO HYPOTHALAMIC DIABETES INSIPIDUS: AN INVESTIGATION INTO POSSIBLE MECHANISMS RESPONSIBLE FOR POLYURIA

A young patient developed hypothalamic diabetes insipidus due to histiocytosis in infancy and was satisfactorily treated with Pitressin. As a teenager she no longer had thirst or polyuria after treatment was stopped. These symptoms only returned during her two pregnancies. When non-pregnant her urine output was 1.7-2.0 1/24 h, basal plasma osmolality 288-290 mOsm/kg, and during pregnancy 24 h urine volume was 4.5-5.21, plasma osmolality 278-280 mOsm/kg. Studies on osmoregulation of thirst and AVP release, and on renal sensitivity to the V2 agonist desmopressin and endogenous vasopressin were performed in pregnant and non-pregnant states. She had no circulating antibodies to AVP, and the effect of pregnancy-associated vasopressinase was eliminated. Results showed lowered basal plasma osmolality and osmolar thirst threshold in pregnancy but no failure of the renal concentrating mechanism. Plasma AVP concentrations after osmotic stimulation were lower in pregnancy. We propose that she developed thirst and polyuria during pregnancy because of lowering of her osmolar thirst threshold to plasma osmolalities which caused her to drink sufficient quantities of fluid to further reduce AVP secretion. We cannot exclude, however, the possibility that there was increased clearance of circulating AVP.     

Syndrome of inappropriate antidiuresis in the absence of arginine vasopressin

The syndrome of inappropriate antidiuresis (SIAD) is usually associated with inappropriately elevated plasma arginine vasopressin (AVP) concentrations. We describe herein a patient with a macroprolactinoma who had symptomatic hyponatremia due to SIAD. Although the patient had excessive thirst, severe plasma hypoosmolality, and hyperosmolar urine, no immunoassayable AVP could be detected. During long term treatment with bromocriptine, there was gradual shrinkage of the prolactinoma coincident with improvement in the ability to excrete a water load and normalization of the thirst threshold. At this point, plasma immunoactive AVP was measurable during a hypertonic saline infusion for the first time. By high pressure liquid chromatographic analysis, this immunoactive substance coeluted with AVP. These studies suggest that the SIAD in this patient was due to the production of an antidiuretic substance distinct from AVP in association with his prolactinoma.     

Thirst and plasma levels of vasopressin, angiotensin II and atrial natriuretic peptide in patients with non-insulin-dependent diabetes mellitus

To clarify a possible mechanism whereby the perception of thirst may be associated with diabetes mellitus, we measured plasma levels of vasopressin (AVP), angiotensin II (ANG II), atrial natriuretic peptide (ANP) and plasma renin activity (PRA) in non-insulin-dependent (NIDDM) diabetic patients with or without thirst. Thirteen male NIDDM patients complaining of thirst had a significantly high blood hematocrit, plasma urea nitrogen and creatinine concentrations and plasma osmolality, indicating a reduction in plasma volume. In addition, the patients had a significantly high mean plasma concentrations of AVP (3.20 +/- 1.27 pmol/l) ANG II (33.8 +/- 31.4 pmol/l) and PRA, but a low mean plasma ANP concentration (8.9 +/- 4.5 pmol/l). After treatment with diet and/or sulfonylurea, plasma levels of AVP, ANG II and PRA decreased with a concomitant increase in plasma volume and disappearance of thirst. In contrast, 13 NIDDM patients (9 females and 4 males) without thirst had normal plasma urea nitrogen and creatinine concentrations, and the hematocrit did not change significantly after treatment. Plasma AVP (0.95 +/- 0.34 pmol/l), ANG II (14.7 +/- 8.8 pmol/l) and ANP (10.7 +/- 4.9 pmol/l) concentrations, and PRA were normal in this group of patients. There was no significant difference between the two groups of patients, however, in fasting glucose concentration and HbA1c. We conclude from these results that a reduction in plasma volume may be the major factor responsible for the induction of thirst sensation and for increased AVP secretion in NIDDM patients. The mechanism underlying a reduction in plasma volume remains unclear.     

Objective assessment of thirst recovery in patients with adipsic diabetes insipidus

Adipsic diabetes insipidus (ADI) is characterised by impaired thirst and defective AVP secretion. We have assessed the thirst response to graded osmotic stimulation using a visual analog scale (VAS) in patients with a history of ADI following surgery for a craniopharyngioma. The patients were thought to be regaining their thirst response but we wanted to confirm that this was the case objectively before relaxing their strict fluid balance regimen. Three patients with adipisa in the presence of hypernatremia following surgery for a craniopharyngioma are described. Their median age at surgery was 13 years (range 11–15 years). All patients had previously demonstrated no desire to drink despite a serum osmolality in excess of 300 mOsmol/kg. Fluid balance was maintained postoperatively with a regimen involving a fixed daily fluid intake and DDAVP dose together with daily weights and regular assessment of capillary sodium concentrations. Patients were thought to be regaining thirst sensation and so were assessed by hypertonic saline infusion (HSI) with thirst measured using a VAS. Patients underwent a HSI test 4, 6 and 9 months post surgery. All had abnormally low AVP production at raised plasma osmolalities but the visual analogue scale confirmed partial or complete thirst recovery. The intensive regimen used to maintain stable serum sodium concentrations was relaxed without the patients subsequently developing a significant hyperosmolar state. We have shown objective recovery of thirst perception in patients with adipsia within 9 months of surgery, despite persistence of cranial diabetes insipidus. These observations indicate that both osmoreceptors regulating thirst and their efferent pathways demonstrate more plasticity than those regulating AVP production. The HSI and thirst VAS are an objective way of assessing patients known to have ADI who are thought to be recovering thirst perception.     

Disturbance of osmoregulated thirst and vasopressin secretion in thyrotoxicosis

OBJECTIVE: To assess the effect of untreated thyrotoxicosis on osmoregulated thirst sensation and AVP secretion. DESIGN: Measurements were made at 30-minute intervals while untreated thyrotoxic patients were given sodium chloride 855 mmol/l intravenously for 2 hours followed by water drinking ad libitum for 2 hours. The protocol was repeated when the patients were euthyroid. PATIENTS: Eight newly diagnosed thyrotoxic patients were studied. MEASUREMENTS: Thirst sensation (visual analogue scale), plasma osmolality, AVP and plasma renin activity were measured. RESULTS: Prior to osmotic stimulation and after plasma osmolality had been returned to normal by drinking water, thirst sensation was increased in the thyrotoxic state. Plasma AVP showed an exaggerated response to hypertonic saline in the patients when they were thyrotoxic. Increasing plasma osmolality produced a linear increase in thirst sensation and log linear increase in plasma AVP. However, in the thyrotoxic state both these relations were altered. The apparent osmolar thresholds for onset of thirst sensation and AVP release were similar (281 and 280 mosm/kg respectively) and were reduced similarly in the thyrotoxic state (269 and 274 mosm/kg respectively). CONCLUSIONS: The osmostat mechanisms which regulate thirst sensation and AVP release are reset in the thyrotoxic state. The responses of thirst sensation and of plasma AVP to increasing plasma osmolality are altered similarly, suggesting that thyrotoxicosis affects both homeostatic functions by a common mechanism.     

Vasopressin and thirst in patients with posterior pituitary ectopia and hypopituitarism

OBJECTIVE: Partial diabetes insipidus has been documented in patients with congenital hypopituitarism and posterior pituitary ectopia, some cases being clinically silent except for enuresis. The objective of our study was to evaluate vasopressin (AVP) secretion and thirst appreciation in hypopituitary patients with posterior pituitary ectopia. PATIENTS: Twelve males and three females, aged between 13 and 38 years (median 19 years). Eleven had multiple pituitary deficiencies, adequately replaced at the time of the study, and four were only growth hormone deficient. None of the patients suffered from polyuria, polydipsia or nocturnal enuresis. We tested the patients with a 5% NaCl infusion. Five patients with abnormal vasopressin production were also tested with nitroprusside, which affects baroceptor vasopressin secretion. RESULTS: We found that only two out of 12 patients had normal AVP secretion. Thirst assessment showed severe hypodipsia in one patient, hyperdipsia in three out of 15 and more subtle abnormalities in two out of 15 patients. Concordance was found between osmotically and baroceptor-stimulated vasopressin. CONCLUSIONS: Patients with posterior pituitary ectopia showed a high prevalence of subclinical subnormal vasopressin response to the osmolar stimulus and moreover an impairment of thirst appreciation. Our data on nonosmotically stimulated AVP release suggest the existence of a damage in the hypothalamic vasopressin secreting centres.     

Osmoregulatory adaptation in pregnancy and its disorders.

The physiological osmoregulatory adaptations of pregnancy include decreased thresholds for both thirst and AVP secretion and increased MCR for AVP. The combined effects of these changes may unmask subclinical DI. In view of the altered relationship between serum osmolality and thirst, caution is required in investigating thirst and polyuria in pregnancy lest an erroneous diagnosis of psychogenic polydipsia be made.     

Diagnosis and management of central diabetes insipidus in adults

Central diabetes insipidus (CDI) is characterized by hypotonic polyuria due to impairment of AVP secretion from the posterior pituitary. In clinical practice, it needs to be distinguished from renal resistance to the antidiuretic effects of AVP (nephrogenic DI), and abnormalities of thirst appreciation (primary polydipsia). As nephrogenic diabetes insipidus is rare in adults, unless they are treated with lithium salts, the practical challenge is how to differentiate between CDI and clinical disorders of excess thirst. The differential diagnosis is usually straight forward, but the recommended gold standard test, the water deprivation test, is not without interpretative pitfalls. The addition of the measurement of plasma AVP concentrations improves diagnostic accuracy, but the radioimmunoassay for AVP is technically difficult, and is only available in a few specialized centres. More recently, the measurement of plasma copeptin concentrations has been claimed to provide a reliable alternative to measurement of plasma AVP, without the sampling handling challenges. In addition, the measurement of thirst ratings can help the differentiation between CDI and primary polydipsia. Once the diagnosis of CDI is biochemically certain, investigations to determine the cause of AVP deficiency are needed. In this review, we will outline the diagnostic approach to polyuria, revisit the caveats of the water deprivation test and review recent data on value of adding AVP/copeptin measurement. We will also discuss treatment strategies for CDI, with analysis of potential complications of treatment.     

Osmotic and non-osmotic regulation of thirst and vasopressin secretion in patients with compulsive water drinking

OBJECTIVE: To examine the osmotic and non-osmotic regulation of thirst and AVP release in patients with compulsive water drinking. DESIGN: A 2-hour intravenous infusion of hypertonic (855 mmol/l) sodium chloride solution, followed by a 2-hour drinking period. PATIENTS: Seven patients with compulsive water drinking, seven patients with diabetes insipidus and seven healthy controls. MEASUREMENTS: Plasma AVP, osmolality, sodium and haematocrit, thirst ratings on a visual analogue scale and the volume of water drunk in 2 hours following infusion. RESULTS: Plasma AVP responses to osmotic stimulation, and non-osmotic inhibition by drinking, were normal in patients with compulsive water drinking. Basal thirst ratings were higher in compulsive water drinking than in either diabetes (P less than 0.001) or controls (P less than 0.001), despite lower basal plasma osmolalities. There was a significant rise in thirst ratings during saline infusion, which correlated closely with plasma osmolality, in all three groups, but the final thirst ratings were higher in compulsive water drinkers, who subsequently drank more water than in either diabetes insipidus (P less than 0.01) or controls (P less than 0.001). Drinking rapidly lowered thirst ratings in controls and diabetes insipidus before changes occurred in plasma osmolality, but remained elevated in patients with compulsive water drinking. Linear regression analysis defined a lower osmotic threshold for thirst in compulsive water drinking compared with controls or diabetes insipidus. CONCLUSIONS: There are abnormalities of the osmotic stimulation and non-osmotic inhibition of thirst in compulsive water drinking, suggesting that the underlying defect is one of interpretation of osmotic and non-osmotic inputs. Measurement of thirst responses during hypertonic saline infusion and subsequent water drinking may provide useful diagnostic information in the differentiation of polyuric states.     

Neuroendocrine, Fluid Balance, and Thirst Responses to Alcohol in Alcoholics

This study simultaneously evaluated multiple circulating neurohormones, osmolality, thirst, and fluid balance in eight actively drinking, alcoholic males and seven controls before and 12 hr after an ethanol challenge. Basal levels of serum osmolality and thirst were significantly higher in alcoholics compared with controls, yet actively drinking alcoholics at the start of the study had normal vasopressin (AVP) levels, plasma angiotensin II (Ang II), plasma renin activity, plasma aldosterone (Aldo), and plasma catecholamines. In response to ethanol, serum osmolalities rose significantly higher while plasma AVP levels became significantly suppressed in alcoholics. After the ethanol stimulus, plasma Ang II levels of alcoholics were significantly higher than those of controls at 11 AM (12.15 +/- 4.49 vs. 1.83 +/- 0.6 pg/ml, p less than 0.02) and 12 noon (14.93 +/- 6.81 vs. 1.37 +/- 0.17 pg/ml, p less than 0.04). Neither plasma renin activity nor Aldo changed in accordance with the elevated plasma Ang II in alcoholics. Diuresis in the alcoholics, assessed by the sum of urine output following the challenge dose, was significantly less than that of controls. Thirst scores and fluid intakes after the ethanol challenge did not differ between alcoholics and controls. The lack of an Ang II-mediated increase in plasma Aldo or thirst response suggests that ethanol may have a specific blunting effect on Ang II receptors. This study demonstrates that ethanol can be used as a provocative test in chronic alcoholics to uncover aberrant hormonal responses for two systems, namely, Ang II and AVP.(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical insights into adipsic diabetes insipidus: a large case series

OBJECTIVE: Adipsic diabetes insipidus (DI) causes significant hypernatraemia. Morbidity and mortality data for patients with adipsic DI have been previously published as single case reports, rather than as formal trials or case series from units with established management protocols. Our objective was to describe morbidity and mortality in patients with adipsic DI attending a tertiary referral centre, representing the largest reported series of adipsic DI, and to suggest management protocols for such patients, based on our extensive experience of this condition. DESIGN: Arginine vasopressin (AVP) responses to hypotension were recorded during trimetaphan infusion. Sleep abnormalities were identified using overnight oximetry or polysomnography. Case-note analysis defined other clinical abnormalities including seizures and thrombotic episodes. Important clinical points for the management of these patients are highlighted. PATIENTS: Thirteen patients with adipsic DI defined by thirst and plasma AVP responses to hypertonic saline infusion. RESULTS: All patients had absent AVP and thirst responses to osmotic stimulation, with subnormal water intake. Five patients had absent AVP responses to hypotension; the remainder had normal responses. Eight patients were obese [body mass index (BMI) > 30 kg/m(2)], and three were overweight (BMI > 25 kg/m(2)). Seven patients had sleep apnoea, of whom three died at 36 years or younger. Four patients developed venous thrombosis during episodes of hypernatraemia. Two patients had thermoregulatory dysfunction and seven patients had seizure activity. CONCLUSION: Adipsic DI is associated with significant morbidity and mortality. Physicians should be aware of associated, treatable hypothalamic abnormalities such as obesity, sleep apnoea, seizures and thermoregulatory disorders when managing adipsic DI.     

Pathophysiology of transient cranial diabetes insipidus during pregnancy

OBJECTIVE We investigated the possible mechanisms underlying transient cranial diabetes insipidus during pregnancy. DESIGN AND PATIENTS A woman who developed clinical diabetes insipidus during the third trimester of pregnancy was studied through a total of three pregnancies and postpartum MEASUREMENTS Plasma AVP, urine and plasma osmolality, urine volume and specific gravity were measured during water deprivation tests and hypertonic saline infusion. Plasma and urine osmolality were measured after subcutaneous injection of AVP. The water deprivation and AVP test were repeated after proven inhibition of urinary PGE₂ with aspirin. Serum vasopressinase activity was measured during one of the pregnancies affected with diabetes insipidus and compared with that obtained between 26 and 38 weeks from 13 normal pregnancies. RESULTS The patient was found to have cranial diabetes insipidus which responded to low dose intranasal 1-desamino-8-D-arginine vasopressin. Inhibition of PGE2 with aspirin did not enhance urine concentrating ability or the response to a test dose of subcutaneous AVP. Plasma levels of vasopressinase remained within the physiological range for normal pregnancy. CONCLUSIONS These studies indicate that subclinical cranial diabetes insipidus may be unmasked in late pregnancy. This effect is not related to AVP resistance resulting from PGE₂ production or excessive vasopressinase activity, but may be due to a combination of physiological vasopressinase secretion with reduced AVP secretory capacity and reduction in the thirst threshold that accompanies normal pregnancy. We relate these findings to a previously described group of women with transient diabetes insipidus during pregnancy who had impaired liver function     

Radioimmunoassay of (8-arginine)-vasopressin. II. Application to determination of antidiuretic hormone in urine.

A radioimmunoassay for [8-arginine]-vasopressin (AVP), previously described (Czernichow et al. 1975) has been used for the determination of antidiuretic hormone in a 4 ml urine sample. AVP is extracted from acidified urine with a cation exchanger (Amberlite CG 50) with an overall recovery of 72%. The blank value measured in extracted samples of urine was 0.29 pg/ml +/- 0.21 (SEM) and calculated by extrapolation of the regression line of the recovery experiment was 0.49 pg/ml. The coefficient of variation within-assay was 13% and between-assay 18%. Addition of the amounts of AVP found in each specimen of urine voided gave results nearly identical to those of the amounts found in 24 h pool of urine, indicating that the assay was not affected by changes in concentration of the other urinary components during the day. The daily urinary excretion of AVP measured in 34 subjects was found to be 34 ng in 17 women and 70 ng in 17 men, a significant difference. Urinary concentration and excretion rate of AVP rose during thirst test and during Carter-Robbins test performed in 13 healthy subjects. In the latter test it was observed that the women displayed a strikingly more pronounced AVP elevation after the osmolar stimulus than the men. In both sexes a significant correlation was found between AVP excretion rate and plasma osmolality as well as free water clearance. Three cases of complete or incomplete diabetes insipidus and potomania could be clearly differentiated according to the total output of AVP during the thirst test. Extremely high values of AVP were found in the urine of 5 subjects with Schwartz-Bartter syndrome associated with bronchogenic tumours.     

OSMOREGULATION OF THIRST AND VASOPRESSIN SECRETION IN KALLMANN''S SYNDROME

It has been suggested that abnormalities of thirst and vasopressin secretion commonly coexist with Kallmann's syndrome. Out-patient plasma osmolality, plasma sodium and 24-hour urine volume were similar in 10 patients with Kallmann's syndrome and 10 matched controls. Six patients underwent dynamic testing of osmoregulation with hypertonic sodium chloride infusion. There were similar rises in plasma AVP concentration in patients (0.4 +/- 0.1-6.2 +/- 1.2 pmol/l, P less than 0.001) and controls (0.4 +/- 0.1-5.7 +/- 1.0 pmol/l P less than 0.001). Thirst ratings rose in similar fashion in patients (0.7 +/- 0.3-6.2 +/- 1.0 cm, P less than 0.001) and controls (1.0 +/- 0.3-7.2 +/- 0.5 cm. P less than 0.001). Drinking rapidly abolished thirst and lowered AVP concentrations in both groups before major changes in plasma osmolality occurred. Linear regression analysis defined similar osmotic thresholds for thirst onset and vasopressin release in the two groups, and there was no difference in the calculated sensitivity of the osmoreceptor/vasopressin secretory unit as defined by the slopes of the regression lines. We conclude that osmoregulation is normal in Kallmann's syndrome.     

Arginine-vasopressin in essential hypernatremia

Dynamics of AVP secretion in a 14-year-old girl with essential hypernatremia, psychomotor retardation and optic nerve coloboma, are reported. Basal levels of AVP were similar to those of a control population, but disproportionately low in relation with natremies. Hypertonic saline and hydric restriction did not alter the AVP basal values, which were, instead, stimulated with orthostatism. AVP decreased during a water surcharge, but delayed elimination of water was observed. The existence of a moderate volume deficit, not corrigible with a chronic surcharge of water, together with the reversed diurnal pattern of water excretion and the AVP data, suggest--as a physiopathological basis of the syndrome--a severe anomaly of the osmoreceptors, with alteration of thirst and of the osmodependent AVP responses, so that the AVP secretion was regulated exclusively through volumetric mechanisms.     

Baroregulation of vasopressin release in adipsic diabetes insipidus

Adipsic diabetes insipidus (ADI) occurs in association with a heterogeneous group of conditions. We report vasopressin (AVP) responses to hypotension in nine patients with ADI and nine controls. Hypertonic saline infusion produced absent thirst (1.7 +/- 1.7 to 1.5 +/- 1.7 cm, P = 0.99) and AVP responses (0.3 +/- 0.1 to 0.4 +/- 0.1 pmol/liter, P = 0.99) in the ADI group, who also drank less than the control group (258 +/- 200 ml vs. 1544 +/- 306 ml, P < 0.001). Intravenous infusion of trimetaphan camsylate produced a fall in mean arterial pressure of 31.6% +/- 8.9% in patients and 29.4% +/- 6.1% in controls. Plasma AVP concentrations rose from 1.4 +/- 0.8 to 340.3 +/- 497.4 pmol/liter (P < 0.001) in the control group. In three patients with craniopharyngioma, there was no rise in plasma AVP concentrations (0.3 +/- 0.1 to 0.3 +/- 0.1 pmol/liter, P = 0.96), but plasma AVP rose significantly in response to hypotension in the other six patients (0.4 +/- 0.2 to 204.5 +/- 223.2 pmol/liter, P < 0.001). We concluded that the AVP responses to hypotension in ADI are heterogeneous and reflect the site of the lesion causing the diabetes insipidus.     

Hypernatremia in a non insulin dependent (type 2) diabetic patient with central diabetes insipidus

We describe a patient with central diabetes insipidus who presented with hyperosmolar, non-ketotic hyperglycaemia. The role in this case of reduced thirst sensation with decreased water intake and abnormal AVP production illustrates the importance of these protective mechanisms in normal physiology regarding maintenance of normal plasma osmolality. Despite the complex pathophysiology in this patient, fluid resuscitation aimed at normalisation of the water deficit resulted in full recovery.     

Chronic hypernatremia derived from hypothalamic dysfunction: impaired secretion of arginine vasopressin and enhanced renal water handling.

We analyzed the disorder of water metabolism in a 32 year-old female with chronic hypernatremia. She had meningitis at 4 years, and ventriculo-peritoneal shunt operation at 13 years because of normal pressure hydrocephalus. At 14 years hypernatremia of 166 mmol/l was initially found and thereafter hypernatremia ranging from 150 to 166 mmol/l has been persisted for the last 18 years. Physical and laboratory findings did not show dehydration. Urine volume was 750-1700 ml per day and urinary osmolality (Uosm) 446-984 mmol/kg, suggesting no urinary concentrating defect. Plasma arginine vasopressin (AVP) levels ranged from 0.4 to 1.2 pmol/l despite hyperosmolality of 298 through 343 mmol/kg under ad libitum water drinking. There was no correlation between plasma osmolality (Posm) and plasma AVP levels, but Uosm had a positive correlation with Posm (r=0.545, P < 0.05). Hypertonic saline (500 NaCl) infusion after a water load increased Uosm from 377 to 679 mmol/kg, and plasma AVP from 0.2 to 1.3 pmol/l. There was a positive correlation between Posm and plasma AVP levels in the hypertonic saline test (r=0.612, P<0.05). In contrast, an acute water load (20 ml/kg BW) verified the presence of impaired water excretion, as the percent excretion of the water load was only 8.5% and the minimal Uosm was as high as 710 mmol/kg. Urinary excretion of aquaporin-2 remained low in concert with plasma AVP levels. No abnormality in pituitary-adrenocortical function was found. These results indicate that marked hypernatremia is derived from partial central diabetes insipidus and elevated threshold of thirst, and that enhanced renal water handling may contribute to maintenance of body water in the present subject.     

Impaired vasopressin secretion in patients with myotonic dystrophy

Hypernatremia has occasionally been observed in patients with myotonic muscular dystrophy (MyD). To elucidate the possibility of osmoregulatory dysfunction, we investigated hypothalamo-posterior pituitary function as well as serum electrolytes in eight patients with MyD. Blood samples were obtained early in the morning after overnight dehydration. Renal function was estimated by blood urea nitrogen, serum creatinine and creatinine clearance. Posterior pituitary function was evaluated by direct measurement of plasma vasopressin (AVP) during a 5% hypertonic saline infusion. Plasma AVP concentrations were determined by sensitive radioimmunoassay. In five patients, circulating blood volume (CBV), plasma renin activity (PRA) and serum aldosterone (S-Aldo.) were also measured. The mean serum sodium level (143.9 +/- 1.7mEq/1: Mean +/- SD) was significantly higher than in the controls (139.4 +/- 2.2mEq/1). A 5% hypertonic saline infusion showed a subnormal increase in AVP and diminished thirst, despite sufficient elevation of plasma osmolality, in all patients as compared with healthy adults. Renal function was intact. Biochemical evidence of dehydration, estimated by PRA, S-Aldo and CBV, was unremarkable in four of the five patients. These findings suggest that patients with MyD have neurogenic disorders of osmoregulation in addition to previously reported endocrine abnormalities. Impaired AVP secretion in response to osmotic stimuli and reduced thirst might be responsible for such failure.     

Water metabolism disturbances at different stages of primary thyroid failure

The aim of the present study was to study salt and water metabolism in thyroid deficiency. We performed an oral water loading test (OWL) and a hypertonic 5% saline infusion test (HSI) in 16 patients with overt primary hypothyroidism before replacement treatment (PRE group) and after, in eight patients with subclinical hypothyroidism (SUB group) and in 16 normal individuals (CG group). In the PRE group, a lower free water clearance was detected in the OWL (P < 0.022), with lower plasma osmolality (OWL: P < 0.005; HSI: P < 0.001) and arginine vasopressin (AVP) (OWL: P < 0.001; HSI: P < 0.001) than the CG group, across both tests; they normalized with the replacement treatment. The same plasma abnormalities were detected in the SUB group with the HSI. Although the AVP and thirst thresholds did not differ between the groups, the lag between them was lower in the PRE (4.1+/-3.2 mOsm/kg) and SUB group (2.6+/-2.1 mOsm/kg) than in the CG group (13.3+/-9.2 mOsm/kg) (P < 0.05). There were no differences in atrial natriuretic hormone (ANH), plasma renin activity (PRA) and plasma aldosterone among the groups. These results indicate that plasma hypo-osmolality and low levels of AVP are present in primary hypothyroidism, and indeed are already present in the subclinical phase of the disease. An overlap between the thresholds of thirst and AVP seem to play a role in these abnormalities, but ANH, PRA and plasma aldosterone do not appear to contribute.