A CASE OF ''ESSENTIAL'' HYPERNATRAEMIA DUE TO RESETTING OF THE OSMOSTAT

We describe a 24-year-old short, obese girl who has bizarre episodic neurological abnormalities related to hyperosmolality due to hypernatraemia. Investigation of osmoregulation by water loading and infusion of hypertonic saline revealed (i) hypodipsia with thirst onset raised to plasma osmolality of 332 mmol/kg and (ii) elevation of the threshold for vasopressin release (plasma osmolality 320 mmol/kg) but normal slope of the plasma vasopressin-plasma osmolality curve. Baroregulated vasopressin release was also grossly subnormal. Other hypothalamo-pituitary investigations showed deficiencies of releasing hormones for gonadotrophins and growth hormone, but prolactin response to combined hypoglycaemia and TRH was blunted She demonstrated other anomalies including hyperlipoproteinaemia and defective lymph drainage of the legs. Skull X-rays, together with computerized tomography and nuclear magnetic resonance scans of the hypothalamo-pituitary region and the rest of the brain were normal. We believe that this is the first case of essential hypernatraemia documented with direct evidence of resetting of the osmostat.     

Idiopathic, sustained, inappropriate secretion of ADH with associated hypertension and thirst.

A 15 year old girl presented with excessive thirst and hypertension (170/110 mm Hg). Biochemical investigations revealed serum sodium 118 meq/liter, serum osmolality 238 mosmol/liter, urine sodium 90 meq/liter, urine osmolality 700 mosmol/liter, persistenly elevated serum antidiuretic hormone (ADH) levels (5.8 to 11.9 pg/ml) and no obvious cause for the hypertension. The hypertension is, at least in part, volume-related, diminishing with fluid restriction. Features of gross water intoxication (e.g., confusion, coma) have not occurred. The etiology of the inappropriate secretion of ADH is not obvious but is not thought to be due to "resetting of osmoreceptors" as evidenced by failure to maximally dilute urine following a water load test and persistently elevated serum ADH levels. A similar patient described by Epstein and associates in 1962 is presently well with persistent features of inappropriate secretion of ADH.     

Effect of thirst challenge on ADH levels in patients with bilateral Menière's disease

The aim of the study was to investigate plasma ADH levels and plasma/urine osmolality in patients suffering from bilateral Menière's disease since a disturbance in the water household after thirst challenge is a suspected pathogenic factor in the development of this disease. In this study the plasma ADH levels and plasma/urine osmolality of bilateral Menière's disease patients under thirst challenge were investigated to show whether the water balance is affected. 9 patients with bilateral Menière's disease and 9 healthy controls skipped water intake for 12 h. Plasma ADH, plasma/urine osmolality, and electrolytes were measured after this thirst period as well as 8 h later after food and fluid intake. During food and fluid intake the patients demonstrated a slightly higher plasma ADH level and plasma osmolality than controls, whereas at the end of the thirst period patients and the controls showed no significant change. Instead the urine osmolality differed significantly (p<0.001): showing a high urine osmolality in controls and an almost stable urine osmolality in patients after thirst challenge. This indicates that the water balance in patients is likely different from that of controls. These observations point to ADH and its target aquaporine 2 as keyplayers in the pathophysiological events leading to the development of Menière's disease.     

The syndrome of inappropriate antidiuretic hormone secretion (SIADH): pathophysiologic mechanisms in solute and volume regulation.

1. Studies on eight patients were performed to clarify the mechanism(s) of altered sodium metabolism and volume regulation in SIADH. The mechanism controlling water excretion was also studied to determine whether there is evidence that altered osmoregulation may be the basis for inappropriate ADH secretion in some patients. 2. These studies show that cumulative sodium balance and aldosterone secretion rates in patients with SIADH are negatively correlated with water intake. There is also a negative correlation between aldosterone secretion and urinary sodium excretion. In the absence of normal urine diluting ability, this increased excretion of sodium becomes a mechanism that allows an increased quantity of water to be excreted despite the persistence of an ADH effect on the renal tubules. 3. Within the range of hyponatremia observed in our studies, changes in serum sodium concentration were accounted for by changes in solute and water balance. One patient, who was potassium deficient during the studies, retained large quantities of sodium and potassium that could not be accounted for by an increase in either serum osmolality or body weight. These observations suggest that intracellular osmotically active solute is either lost or "inactivated" in some manner as intracellular potassium is replenished. 4. Marked impairment of urine diluting ability was demonstrated in all patients. However, two patients with SIADH associated with pulmonary tuberculosis exhibited graded responses to water loading, which suggests that ADH secretion may have been suppressed as serum osmolality was progressively reduced. Whether this can be attributed to a basic alteration or "re-setting" or osmoreceptor function, or is merely an indication that greater than normal reductions of serum osmolality are required to inhibit potent nonosmotic stimuli, remains to be determined.     

Disorders of urinary concentration and dilution

A new approach to the classification of disorders of urinary concentration and dilution is recommended based on recent studies of how the kidney elaborates a urine of widely varying osmolality. The capacity to concentrate urine depends on f_T, the fractional reabsorption of solute delivered to the loop of Henle; f_U, the excretion of solute relative to the sum of solute excretion and solute delivery to Henle's loop; f_W, the fraction of solute loss by vascular outflow from the medulla relative to that reabsorbed by the loop; and finally, collecting duct response to antidiuretic hormone (ADH). A decrease in f_T or an increased f_U or f_W will diminish urinary concentrating ability, as will resistance of the tubule to ADH. Conversely, urinary dilution depends on the delivery of sodium and water to the ascending limb; NaCl reabsorption by the ascending limb; and the absence of ADH. A decrease in sodium and water delivery to the ascending limb or in NaCl reabsorption by the ascending limb will impair urinary diluting ability, as will the presence of ADH. The consequences of disorders in urinary concentrating and diluting ability vary widely. In an alert patient with an intact thirst center, there may be no consequence; in a patient unable to communicate thirst or whose thirst center is deranged, the results may be catastrophic. Keeping in mind the kidney's few basic requirements for formation of concentrated or dilute urine may help the physician avoid these potentially serious dislocations of water balance.     

Acute water intoxication as complication of intravenous urography

Physiologically, two complementary mechanisms regulate plasma osmolality: antduretic hormone ADH) and thirst. ADH release s supressed, thirst s inhbted and renal water loss occurs when plasma osmolality below a threshold level. The rise in plasma osmolalty causes ADH release, stimulation of thirst and water intake. Acute water intoxication is exceptional in patients without a chronic psychiatric disease. Herein, we describe a case of acute water intoxication in a previously healthy patient, after making an intravenous urography. The excessive water intake and the impossibility of renal water loss because of streee-induced ADH release originated t. Only nine cases have been previously described; almost they all were women preparing for diagnostic procedures.     

Hypodipsia in geriatric patients

Hypernatremia in elderly patients is most often due to the patients' mental incapacity or physical inability to obtain water despite intact thirst sensation. Hypodipsia leading to hypernatremia is not often considered in alert, elderly subjects since hypodipsia is not a recognized consequence of nonaphasia-producing cerebrovascular accidents. Described herein are six elderly patients who had such cerebrovascular accidents and who had recurrent hospitalizations for dehydration and hypernatremia. Hypernatremia in this group was due to hypodipsia and could only be prevented by prescribing daily fluid intake as a medication order. Hypodipsia should be considered as a cause of hypernatremia in elderly subjects even when they seem fully capable of requesting and obtaining water.     

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.     

Symptomatic normovolemic essential hypernatremia. A clinical and physiologic study

A 23 year old man presenting with episodic muscle paralysis and persistent normovolemic hypernatremia and hyperosmolality was investigated. Metabolic studies at the time of presentation and during a 10 hour fast, and the responses to acute and chronic water loading, alcohol, vasopressin and nicotine infusion, sodium restriction and intravenous sodium loading were all normal, with the exception of the acute water load. These results suggested abnormal hypothalamic function leading to an altered regulation of the central osmoreceptors controlling thirst and sodium metabolism; however, no central nervous system lesion was demonstrable. Despite normal levels of plasma [potassium], total exchangeable body potassium was reduced. It is proposed that the muscle paralysis was secondary to both the hypernatremia and the reduced total body potassium status. Progressive symptomatic improvement with lowering of plasma sodium and osmolality occurred following 24 months on a low sodium-high potassium-high fluid regimen although total body potassium status has remained low.     

Drug-induced syndrome of inappropriate diuresis or of antidiuretic hormone secretion?

The syndrome of inappropriate secretion of antidiuretic hormone (SIADH) (Bartter and Schwartz, 1967) is defined as low effective plasma osmolality due to impaired renal water dilution together with impaired thirst center regulation once effective hypovolemia and corticotropin deficiency are ruled out (Robertson, 2006).Impaired water dilution is encountered following stimulation of voloreceptors triggering ADH (i.e., vasopressin) secretion through brain circumventricular organ stimulation [including notably the subfornical organ (SFO)] (Bichet, 2019). This condition is reversed as soon as volemia is restored: hyponatremia is corrected within hours, unlike withdrawal of drugs inducing SIADH, in which optimal water dilution recovery usually takes several days or weeks. Therefore, diuretics will be beyond the scope of this review.     

Altered water metabolism in tuberculosis: role of vasopressin

PURPOSE: Patients with hyponatremia due to tuberculosis have shown variable responses to water loading in previous small studies, ranging from persistent antidiuresis to a normal diuresis. Although tuberculosis is considered a cause of the syndrome of inappropriate antidiuretic hormone secretion (SIADH), circulating vasopressin has been documented in only a few cases. We studied a larger group of patients to determine whether it can be suppressed by a short-term reduction in osmolality. PATIENTS AND METHODS: Twenty-eight hyponatremic patients (mean age +/- SD: 40 +/- 10 years) with pulmonary or miliary tuberculosis underwent a clinical evaluation, measurement of blood and urine chemistry values, and (in 22) a water load of 20 mL/kg. Volume status was evaluated by urine sodium concentration, blood and urine urea nitrogen, and plasma renin activity. Endocrine, renal, and other recognized causes of SIADH were excluded. RESULTS: All 22 patients exhibited a decline in urine osmolality and an increase in free water clearance after water loading. Water excretion was fully normal in seven of 22, with the remainder showing variable impairment of diluting ability and/or volume excreted. Plasma vasopressin, measured in 11 of 22 patients as well as in six others not subjected to water loading, was detectable despite hypo-osmolality in 16 of 17. Vasopressin levels declined after water loading, from 1.85 +/- 1.32 to 0.77 +/- 0.25 pg/mL (p less than 0.05). The majority of patients had the euthyroid sick syndrome but normal adrenal responses to cosyntropin. Although several patients had mild volume depletion when studied, this factor did not appear to explain the defect in water excretion. Hyponatremia resolved predictably within days to weeks of antituberculous therapy. CONCLUSIONS: Circulating vasopressin remains detectable in hyponatremic patients with tuberculosis and is responsive to changes in osmolality. A downsetting of osmoregulation induced by active tuberculosis ("reset osmostat") could explain this abnormality, but we cannot exclude an unidentified non-osmotic stimulus that can be counteracted by water loading.     

Role of endogenous opioids in neurohypophysial function of man

Studies were carried out in normal human subjects to determine the effect of two narcotic antagonists, oxilorphan and butorphanol, on antidiuretic hormone (ADH) release. Oxilorphan given to eight subjects on ad libitum fluid intake resulted in a transient but significant increase in 24-h free water clearance and a decrease in urine osmolality. These changes were not accompanied by an increase in creatinine or solute excretion, and urinary ADH levels did not rise even though plasma osmolality rose significantly from 289.4 +/- 0.9 to 292.9 +/- 0.8 mosmol/kg. Treatment with oxilorphan did not interfere with the response to ADH infusion in water-loaded subjects. Both oxilorphan and butorphanol significantly elevated the plasma osmolality at which ADH release became evident after the infusion of hypertonic saline in water-loaded subjects. Oxilorphan suppressed urinary ADH excretion at the time of the osmotic threshold for ADH release in spite of the greater plasma osmolality. The data indicate that the narcotic antagonists are capable of inhibiting ADH release in man during ad libitum fluid intake and in response to an osmotic stimulus by elevating the osmotic threshold for ADH release. It is concluded that narcotic antagonist inhibition of endogenous opioid action provides further evidence supporting a role for the brain opiates in the normal regulation of neurohypophysial hormone release in man.     

Myelodysplastic syndrome with central diabetes insipidus manifesting hypodipsic hypernatremia and dehydration

Central diabetes insipidus (DI) is a rare but recognized complication of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) that is caused by leukemic infiltration to the hypothalamo-neurohypophyseal system. In rare patients in whom a wide region of the hypothalamus is involved, central DI results in hypodipsic hypernatremia and dehydration. Typical DI symptoms such as polydipsia, polyuria, and marked thirst are concealed in these cases, because the hypothalamic "thirst center" cannot send thirst stimuli to the cerebral cortex. Herein we describe a patient with MDS developing into AML, who presented with hypodipsic hypernatremia and dehydration. A diagnosis of central DI was made on the ground of a low level of serum anti-diuretic hormone (ADH) despite high serum osmolality. A magnetic resonance imaging study revealed attenuation of a physiological "bright spot" of the neurohypophysis. An induction course chemotherapy including regular-dose cytarabine and daunorubicin produced a rapid improvement of hypernatremia. The bone marrow aspirate after two courses of chemotherapy showed complete remission. At that point, ADH release and the "bright spot" were recovered. In order to correctly diagnose central DI in association with hematological malignancies, we should not overlook this atypical type of DI.     

渴感减退性高钠血症病因及治疗探讨——5例报道及去氨加压素疗效观察

目的 渴感减退性高钠血症,又称特发性高钠血症.临床罕见,国内外报道有限,发病机制不详,尚无有效安全的治疗手段.本研究根据本组先前对渴感减退性高钠血症发病机制和治疗的探索,对5例渴感减退性高钠血症患者进行了醋酸去氨加压素的实验性临床治疗,观察对该病的临床缓解效果.方法 5例高钠血症伴有渴感缺失或减退的患者根据Halter等提出的参考标准诊断.对该5例患者进行血尿渗透压、血钠、尿比重、自由水清除率测定和禁水加压实验及水负荷实验,以视觉模拟刻度对渴感等级进行评估,并进行垂体前叶功能评价,所有患者进行强制性每日饮水2 000～2 500 ml,有垂体前叶功能减退者给予相应激素替代补充治疗,1周后在患者高血钠没有缓解的情况下给予醋酸去氨加压素治疗,观察高钠血症和渴感减退的缓解情况.结果 5例患者的血钠水平为160～190 mmol/L,血浆渗透压为330～370 mmol/L,而患者的渴感等级为0～2级.患者均存在部分性中枢性尿崩症,渗透压阈值升高为330～360 mmol/L.强制性每日饮水和垂体前叶激素替代治疗1周后高血钠仍然不能缓解.通过治疗尿崩症的药物醋酸去氨加压素0.05～0.2 mg/d对该5例患者进行试验性治疗5～7天后,发现患者血钠下降,渴感减退也有明显缓解,渴感等级上升为5～7级,且未见明显不良反应.结论 渴感减退性高钠血症存在中枢性部分性尿崩症,醋酸去氨加压素对渴感减退性高钠血症的治疗有效而且安全方便.     

New approach to disturbances in the plasma sodium concentration

Hyponatremia and hypernatremia are among the most common electrolyte disorders. Since the plasma sodium level is determined by the ratio between the total quantity of effective solutes (primarily sodium and potassium salts) and the total body water, abnormalities in the plasma sodium level must be produced by a change in one or more of these parameters. In most patients, alterations in body water are of primary importance because the plasma sodium level is normally regulated by changing water intake and water excretion. Measurement of free water excretion has traditionally been calculated by using a formula that includes the urine osmolality. However, urea is a major urinary solute but does not contribute to regulation of the plasma sodium level, since it is an ineffective osmole. As a result, urinary solute excretion is best expressed as 2 X UNa+K. Making this important correction allows solute and water intake and excretion to be compared, thereby leading to a better understanding of both the development and correction of disturbances in the plasma sodium level.     

Acute infectious pneumonia is accompanied by a latent vasopressin-dependent impairment of renal water excretion

The mechanism of hyponatremia associated with pneumonia has not been definitely established. Moreover, renal water excretion was never systematically investigated in cases of pneumonia without hyponatremia. We therefore studied nine consecutive patients breathing spontaneously (nasal oxygen in five), with acute infectious pneumonia and normal plasma sodium concentration. All the patients were previously healthy. Water loads were administered during illness and after recovery. Extracellular fluid volume, arterial blood pressure, PaO2, and PaCO2 were identical during and after pneumonia. By contrast, renal water excretion was markedly impaired during pneumonia and returned to normal values after recovery. This was attested to by a significant decrease in minimum urine osmolality together with significant increases in the percentage of the excreted water load and the maximum free water clearance, after resolution of the pneumonia. Plasma arginine vasopressin values were significantly higher during pneumonia than after recovery despite similar plasma sodium concentrations, both before and after water load. A positive correlation between plasma arginine vasopressin and minimum urine osmolality was found during pneumonia. Thus, impairment in renal water excretion appeared to be due to resetting of the vasopressin osmostat and could not be attributed to any recognized nonosmotic stimulus for vasopressin secretion. On the other hand, these defects varied in severity depending on the extent of the pneumonia and persisted until clearing of alveolar opacities, accounting for their protracted course in some patients. We conclude that water excretion is impaired in most if not in all patients with acute infectious pneumonia (especially if extended), and that the administration of hypotonic solutions should be avoided in these patients.     

Hypothalamic syndrome with hypernatremia and muscular paralysis

This report describes a twenty-eight year old man with defective thirst sensation and episodes of severe hypernatremia associated with profound weakness and paralysis. The degree of hypernatremia on one occasion (216 mEq/L) is thought to be the highest reported except for cases resulting from accidental salt poisoning. This patient appeared to be unique also in that diabetes insipidus was not present, there was no demonstrable anatomic abnormality of the anteroventral hypothalamus, and the severe degree of hypernatremia encountered could not be explained on the basis of hypodipsia and water deficit alone. The patient exhibited excellent renal concentrating ability with urine specific gravity as high as 1.036 and urinary osmolality as high as 1375 mOsm/kg, abnormal diurnal variation in the excretion of water and sodium, delayed diuresis following a water load; lack of response to rapid intravenous infusion of hypertonic saline solution and continued sodium retention in the presence of hyperosmolality. These findings were interpreted to indicate that his osmoreceptors were relatively insensitive to cellular dehydration and that reliance was placed largely upon volume receptors for regulation of water and electrolyte balance.     

Disorders of body water homeostasis in critical illness.

Disorders of sodium and water homeostasis are among the most commonly encountered disturbances in the critical care setting, because many disease states cause defects in the complex mechanisms that control the intake and output of water and solute. Because body water is the primary determinant of extracellular fluid osmolality, disorders of body water balance can be categorized into hypoosmolar and hyperosmolar disorders depending on the presence of an excess or a deficiency of body water relative to body solute. Because the main constituent of plasma osmolality is sodium, hypoosmolar and hyperosmolar disease states are generally characterized hy hyponatremia and hypernatremia, respectively. After a brief review of normal water metabolism, this article focuses on the diagnosis and treatment of hyponatremia and hypernatremia in the critical care setting.     

Role of antidiuretic hormone in impaired water excretion of patients with congestive heart failure

Plasma antidiuretic hormone (ADH), PRA, plasma osmolality, and the parameters of renal water excretion were measured after overnight dehydration and for 5 h after an oral load in 14 patients with congestive heart failure (CHF) treated with diuretics (group 1), 8 hypertensive patients without CHF also treated with diuretics (group 2), and 11 patients with coronary artery disease but without CHF who were not treated with diuretics (group 3). Under basal conditions, mean plasma osmolality was lower in group 1 than in group 3, but was not different in groups 1 and 2. Mean plasma ADH was higher in group 1 than in group 2 or 3. In response to the water load, plasma osmolality and plasma ADH levels decreased in the 3 groups. ADH levels remained significantly greater in group 1 than in groups 2 and 3 from 2-4 h after the water load despite more marked hypoosmolality in group 1 compared with that in either of the 2 control groups. Plasma ADH was significantly correlated with plasma osmolality only in the 2 control groups. Mean PRA was greater in patients with CHF and patients without CHF treated with diuretics than in untreated patients. Cumulative water excretion was lower in patients with CHF than in patients in the 2 control groups from 2-5 h after the water load. At 5 h, the mean percentage excretion of the ingested loads was 56.8%, 90.7%, and 91.2% in the patients of groups 1, 2, and 3 respectively. Free water clearance was lower and minimal urinary osmolality was greater in the patients with CHF than in those in the 2 control groups. Two patients with CHF, who excreted more than 75% of the water load, also had low plasma basal ADH levels. These data show that patients with CHF have an inappropriate response of plasma ADH to a marked fall in plasma osmolality. This disorder is not due to the diuretic therapy, since hypertensive patients treated with diuretics behaved similarly to untreated patients without CHF. The reasons for this inappropriate response of plasma ADH during a water load in patients with CHF are probably multifactorial.     

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.