Hyperemesis gravidarum followed by refeeding syndrome causes electrolyte abnormalities induced rhabdomyolysis and diabetes insipidus.

Although hyperemesis gravidarum (HG), an extreme form of morning sickness, is a common complication during pregnancy, HG associated simultaneous onset of rhabdomyolysis and diabetes insipidus due to electrolyte abnormalities are rare. A 34-year-old woman with severe HG at 17 weeks of gestation complicated with appetite loss, weight reduction by 17 kg, general fatigue, myalgia, weakness and polyuria was identified to have simultaneous hypophosphatemia (1.6 mg/dL) and hypokalemia (2.0 mEq/L). Appetite recovery and the improvement of the hypophosphatemia (3.2 mg/dL) were observed prior to the first visit to our department. At the admission, she presented polyuria around 7,000~8,000 mL/day with impaired concentrating activity (U-Osm 185 mOsm/L), and abnormal creatine kinase elevation (4,505 U/L). The electrolyte disturbances and physio-metabolic abnormalities in undernourished state due to HG let us diagnose this case as refeeding syndrome (RFS). In this case, abnormal loss by vomiting, insufficient intake and previous inappropriate fluid infusion as well as the development of RFS may accelerate the severity of hypokalemia due to HG. Thus, as her abnormalities were considered as results of rhabdomyolysis and diabetes insipidus due to severe HG associated hypokalemia based on RFS, oral supplementation of potassium chloride was initiated. After 6 days of potassium supplementation, her symptoms and biochemical abnormalities were completely resolved. Severe HG followed by RFS can be causes of electrolyte abnormalities and subsequent complications, including rhabdomyolysis and renal diabetes insipidus. Appropriate diagnosis and prompt interventions including adequate nutrition are necessary to prevent electrolyte imbalance induced cardiac, neuromuscular and/or renal complications.

A history of diabetes insipidus: paving the road to internal water balance.

Diabetes insipidus is an ancient disease considered under the rubric of diabetes, the Greek descriptive term for polyuria, which was unrecognized even after the sweetness of urine was reported as a characteristic of diabetes mellitus in the 17th century. It would be another century before diabetes insipidus was identified from the insipid rather than saccharine taste of urine in cases of polyuria. After its increased recognition, pathologic observations and experimental studies connected diabetes insipidus to the pituitary gland in the opening decades of the 20th century. Simultaneously, posterior pituitary lobe extracts were shown to be vasoconstrictive (vasopressin) and antidiuretic (antidiuretic hormone). As vasopressin was purified and synthesized and its assay became available, it was shown to be released in response to both osmotic and volume stimuli that are integrated in the hypothalamus, and vasopressin thereby was essential to maintaining internal water balance. The antidiuretic properties of vasopressin to treat the rare cases of diabetes insipidus were of limited clinical utility until its vasoconstrictive effects were resuscitated in the 1970s, with the consequent increasing wider use of vasopressin for the treatment of compromised hemodynamic states. In addition, the discovery of antidiuretic hormone receptor blockers has led to their increasing use in managing hypo-osmolar states.

Holoprosencephaly and diabetes insipidus in a 3-month-old infant.

Holoprosencephaly is a developmental defect caused by incomplete cleavage of the embryonic forebrain structures during early embryogenesis. We describe a 3-month-old boy with median cleft palate, surgically reconstructed cleft lip, hypotelorism with a flat nose, cryptorchidism, clubfoot, and microcephaly. During the laboratory investigation, his blood sodium level was 154 mmol/L and urine specific gravity was 1.007. Serum osmolarity was 317 mOsm/kg and urine osmolarity was 268 mOsm/kg. Given these findings and the clinical response to vasopressin, diagnosis of central diabetes insipidus was made. Magnetic resonance imaging revealed semilobar holoprosencephaly. The patient responded very well to vasopressin treatment with restoration of serum electrolytes, which remained within normal limits on follow-up. In case of midline facial defects accompanied by hypotelorism with or without developmental delay, the brain should be imaged to confirm its morphology and investigations should be directed by a high index of suspicion of associated endocrinologic dysfunctions.

Hypothalamic galanin and plasma leptin and ghrelin in the maintenance of energy intake in the Brattleboro rat.

Galanin, ghrelin, and leptin are three peptides involved in feeding regulation and more particularly in fat intake. The Brattleboro (di/di) rat is a genetic model of diabetes insipidus characterized by a preference for fat when it is in a food choice situation. Here, we measured hypothalamic galanin concentrations, plasma ghrelin and leptin and dietary preferences of adult di/di Brattleboro rats, di/+ and Long-Evans controls. The Brattleboro rats weighed significantly less than the di/+ rats (-18%; P<0.001). The fat-to-carbohydrate intake ratio was significantly greater in Brattleboro rats than in di/+ (P<0.02) when the rats could choose between a high-fat diet and a high-carbohydrate diet. Galanin concentrations were significantly lower in di/di rats than in di/+ rats in the paraventricular nucleus (-56%; P<0.001), but not in the arcuate nucleus. Plasma leptin was significantly lower in the di/di rats than in the di/+ rats (3.49+/-0.20 vs. 6.94+/-0.49 ng/ml; P<0.001). Plasma ghrelin concentrations were significantly lower in Long-Evans rats than in the di/di rats (-21%; P< 0.01). Given that galanin mRNA is overexpressed in the paraventricular nucleus of Brattleboro rats, these data are consistent with increased release of the peptide. In the Brattleboro rat, this overactive galanin system and the variations of ghrelin and leptin maintain an orexigenic drive favoring a preferential intake of fat which provides the animal with enough energy for its metabolism.

Prenatal exposure to ethanol causes partial diabetes insipidus in adult rats.

Chronic consumption of ethanol in adult rats and humans leads to reduced AVP-producing neurons, and prenatal ethanol (PE) exposure has been reported to cause changes in the morphology of AVP-producing cells in the suprachiasmatic nucleus of young rats. The present studies further characterize the effects of PE exposure on AVP in the young adult rat, its hypothalamic synthesis, pituitary storage, and osmotically stimulated release. Pregnant rats were fed a liquid diet with 35% of the calories from ethanol or a control liquid diet for days 7-22 of pregnancy. Water consumption and urine excretion rate were measured in the offspring at 60-68 days of age. Subsequently, the offspring were infused with 5% NaCl at 0.05 ml.kg(-1).min(-1) with plasma samples taken before and at three 40-min intervals during infusion for measurement of AVP and osmolality. Urine output and water intake were approximately 20% greater in PE-exposed rats than in rats with no PE exposure, and female rats had a greater water intake than males. The relationship between plasma osmolality and AVP in PE-exposed rats was parallel to, but shifted to the right of, the control rats, indicating an increase in osmotic threshold for AVP release. Pituitary AVP was reduced by 13% and hypothalamic AVP mRNA content was reduced by 35% in PE-exposed rats. Our data suggest that PE exposure can cause a permanent condition of a mild partial central diabetes insipidus.

Hypothalamic-pituitary-adrenal axis up-regulation in rats submitted to pituitary stalk compression.

The present study investigated the hypothalamic-pituitary-adrenal (HPA) axis activity in response to stress in adult male rats submitted to pituitary stalk compression (PSC) or sham operation. Animals received water or oral salt loading (2% NaCl) for one or eight days before the day of the experiment. On the 14th day post-surgery rats were killed under basal conditions or after 15 min immobilization stress. In the PSC group urine output increased significantly and plasma vasopressin (AVP) levels failed to respond to osmotic stimuli. Short-term salt load induced a significant increase in AVP levels in the sham-operated group. The PSC group presented higher adrenocorticotrophin (ACTH) and corticosterone levels compared with sham-operated rats, both in water intake and salt load conditions. Immobilization stress induced a similar increase in plasma ACTH and corticosterone concentrations in sham-operated and PSC groups under water intake. However, long-term salt load blunted the ACTH and corticosterone responses to immobilization stress in sham-operated rats. PSC rats submitted to short- and long-term salt loading presented no changes in ACTH and corticosterone levels after immobilization. Immobilization stress caused neither AVP responses nor plasma osmolality changes in sham and PSC groups. There was no difference in median eminence AVP content among all groups. In conclusion, the high ACTH and corticosterone levels found in PSC rats under water intake and salt loading conditions suggest an up-regulation of the HPA axis, with a preserved adaptive mechanism to chronic stress.

Hypothalamus-pituitary-adrenal axis in central diabetes insipidus: ACTH and cortisol responsiveness to CRH administration.

A strong relationship has been found between arginine-vasopressin (AVP) and hypothalamus-pituitary-adrenal axis in humans. The aim of the current study was to evaluate baseline and CRH-stimulated ACTH and F levels in patients with central diabetes insipidus (CDI), before and after replacement therapy with desamino-D-AVP (DDAVP). Twenty-five patients with CDI, and 25 sex- and age- and BMI-matched healthy subjects entered the study. A standard CRH test (measurement of plasma ACTH and serum F before and every 15 min for 2 h after the administration of 100 microg of human CRH) was performed in all subjects. In patients with CDI, CRH test were repeated after 1 week of DDAVP at standard doses. At study entry, ACTH and F levels were significantly higher in patients with CDI than in controls either at baseline (ACTH: 45.5+/-4.8 vs 18.5+/-3.3 ng/l, p<0.05; F: 375.1+/-55.7 vs 146.6+/-19.4 microg/l, p<0.05) or after CRH test considered as a peak (ACTH: 90.8+/-14.4 vs 42.5+/-7.4 ng/l, p<0.05; F: 501.6+/-65.7 vs 226.3+/- 25.6 microg/l, p<0.05) and AUC (ACTH: 3997.0+/-571.7 vs 2136.0+/-365.8 ng/l/120 min, p<0.05; F: 31,489.0+/-4299.4 vs 14,854.5+/-1541.5 microg/l/120 min, p<0.05). In patients with CDI, 1 week of replacement with DDAVP brought down ACTH (peak: 56.9+/-9.3 ng/l; AUC: 2390.7+/-480.7 ng/l/120 min) and F (peak: 310.3+/-39.5 microg/l; AUC: 17,555.5+/-2008.7 microg/l/120 min) responses to CRH to normal but did not significantly modify baseline hormone levels (ACTH: 29.6+/-3.6 ng/l; F: 239.0+/-32.3 microg/l). In conclusion, CDI is associated to increased baseline ACTH and F levels and increased responsiveness of ACTH and F to CRH administration. In addition, replacement treatment with DDAVP normalized CRH-induced but not baseline ACTH and F secretion.

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.

Ovulation induction with pulsatile gonadotropin-releasing hormone (GnRH) or gonadotropins in a case of hypothalamic amenorrhea and diabetes insipidus.

Hypothalamic amenorrhea is a treatable cause of infertility. Our patient was presented with secondary amenorrhea and diabetes insipidus. Cortisol and prolactin responded normally to a combined insulin tolerance test (ITT) and thyrotropin-releasing hormone (TRH) challenge, while thyroid-stimulating hormone (TSH) response to TRH was diminished, and no response of growth hormone to ITT was detected. Both luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels increased following gonadotropin-releasing hormone (GnRH) challenge. No response of LH to clomiphene citrate challenge was detected. Magnetic resonance imaging findings demonstrated a midline mass occupying the inferior hypothalamus, with posterior lobe not visible and thickened pituitary stalk. Ovulation induction was carried out first with combined human menopausal gonadotropins (hMG/LH/FSH) (150 IU/day) and afterwards with pulsatile GnRH (150 ng/kg/pulse). Ovulation was achieved with both pulsatile GnRH and combine gonadotropin therapy. Slightly better results were achieved with the pulsatile GnRH treatment.

A compartmental model predicts that dietary potassium affects lithium dynamics in rats.

Lithium is the treatment of choice for manic depression, but therapy often results in nephrogenic diabetes insipidus and lithium intoxication. To investigate the effects of dietary potassium on potential side effects of lithium therapy, a mathematical model was built using the modeling program SAAM (Simulation, Analysis, And Modeling). Experimental data modeled were from adult male Sprague-Dawley rats fed diets with or without lithium and one of three levels of potassium for 17 d. A five-compartment model of lithium dynamics was built that was consistent with data from rats fed a lithium-containing diet adequate in potassium. This model was then compared with data from rats fed the other two lithium-containing diets. The model predicts that both the fractional transfer coefficient and rate of transport of lithium to the serum compartment from the kidney compartment are lower in rats fed the potassium-adequate diet than in those fed the potassium-deficient diet, and even lower in those fed the potassium-supplemented diet. In addition, fractional transfer coefficients into the serum compartment from the sampled and simulated tissue compartments changed differently with time depending on the amount of dietary potassium. The model also predicts that there would be less accumulation of lithium in the kidney, sampled tissue and simulated tissue compartments with supplemental dietary potassium. The model suggests that potassium supplementation, after a 7-d delay, protects against nephrogenic diabetes insipidus and the potentially toxic accumulation of lithium by decreasing the reabsorption of lithium from the kidneys and increasing lithium efflux from the tissues.

Lack of satiety effect of cholecystokinin (CCK) in a new rat model not expressing the CCK-A receptor gene.

This work expands recent observations that Otsuka Long-Evans Tokushima Fatty (OLETF) rats show little or no pancreatic expression of the cholecystokinin (CCK)-A receptor gene. We examined whether the CCK-A and -B receptor genes were expressed in the brain (hypothalamus) of OLETF rats in comparison with control (Long-Evans Tokushima Otsuka = LETO) rats. CCK-A receptor mRNA was detected in the hypothalamus of LETO rats but not OLETF rats. The CCK-B receptor gene was expressed in the hypothalamus in both strains. Cerebroventricular administration of CCK-8 sulfate inhibited daily food intake in LETO rats, but not in OLETF rats. These results show that in OLETF rats the absence of CCK-A receptor gene expression in the hypothalamus results in hyperphagia because of lack of satiety.

Detection of vasopressin cell antibodies in some patients with autoimmune endocrine diseases without overt diabetes insipidus.

OBJECTIVE: Cytoplasmic autoantibodies to vasopressin cells (AVP) have been detected in patients with idiopathic central diabetes insipidus and only in one patient with endocrine autoimmune diseases without clinical diabetes insipidus. The aim of this study was to look for AVP cell antibodies (AVP-cell-Ab) in human sera of a large population of autoimmune endocrine disease patients without diabetes insipidus and to test whether an occurrence of these antibodies in some patients can be associated with partial impairment of posterior pituitary function. MEASUREMENT: Sera from 410 patients (310 females, 100 males, age range 10-46 years) with autoimmune endocrine disorders (260 with thyroid autoimmune disease, and 150 with insulin dependent diabetes mellitus) without clinical diabetes insipidus, and from 100 normal subjects, were investigated for hypothalamic autoantibodies by an indirect immunofluorescence method. Positive sera were subsequently tested with specific rabbit anti AVP serum. RESULTS: None of controls, but five out of 410 patients (1.2%) were AVP-cell-Ab positive. All positive and nine negative from the 410 screened patients were tested for posterior pituitary function. Two out of five AVP-cell-Ab positive patients showed partial diabetes insipidus. CONCLUSION: AVP cell antibodies can be shown in some patients with endocrine autoimmune disease without diabetes insipidus and can sometimes be associated with findings of partial posterior pituitary dysfunction. This suggests that clinical diabetes insipidus could be preceded by a long subclinical period characterized only by the occurrence of AVP-cell-Ab in the sera associated or followed by alterations in functional tests. Longitudinal studies are needed to confirm this hypothesis.

Neurohypophysial peptides in the human hypothalamus in relation to development, sexual differentiation, aging and disease.

The two neuronal systems that contain neurohypophysial peptides in the hypothalamus i.e. (i) the supraoptic and paraventricular nucleus and (ii) the suprachiasmatic nucleus, show quite different patterns of changes in the human in relation to development, aging and disease.

Anterior pituitary function and computed tomography/magnetic resonance imaging in patients with Langerhans cell histiocytosis and diabetes insipidus.

In order to document anterior pituitary dysfunction in patients with biopsy-proven Langerhans cell histiocytosis (LCH) and diabetes insipidus and to correlate this with structural changes on imaging, we performed an insulin tolerance test, enhanced computed tomography (CT), and unenhanced magnetic resonance imaging (MRI) in nine patients. Six of the nine patients had growth hormone deficiency, which in two patients was part of panhypopituitarism and in one was associated with poor cortisol response to insulin hypoglycemia. One patient had an exaggerated growth hormone response and one who had had neck irradiation as an infant, had a high resting thyroid stimulating hormone (TSH) suggesting compensated primary hypothyroidism. All enhanced CTs were abnormal, bony defects being the only abnormality in two patients and opaque mastoids in one. The remaining six patients all had structural changes in the hypothalamic/pituitary region. Unenhanced MRI confirmed the CT findings except in one child who had been treated with radiotherapy in the intervening period, but, in addition, confirmed diabetes insipidus by showing absence of the posterior pituitary bright signal and picked up white matter changes in a child with clinical neurological dysfunction. Our findings indicate that the development of diabetes insipidus in LCH is commonly associated with anterior pituitary dysfunction and is usually associated with structural changes in the hypothalamic/pituitary axis.

Ultrastructure of hypothalamic paraventricular neurons.

The hypothalamic paraventricular nucleus (PVN) plays a pivotal role in the regulation of endocrine processes and the modulation of autonomic functions. The multi-channel outputs of the nucleus are directed toward the anterior and posterior lobes of the pituitary, autonomic centers, and limbic structures. Counterbalancing the wide spectrum of efferent projections, the nucleus receives humoral signals from endocrine glands and neuronal afferents from several loci of the brain. The multiple functions of the nucleus are executed by neurons that are organized in distinct subnuclei and display complex chemotypes. The review demonstrates and discusses the organization, architecture, chemical composition, plasticity, and pathology of paraventricular neurons of the rat hypothalamus from the perspective of ultrastructural analysis. Electron microscopy--by its high resolution--offers a powerful tool that is suitable for revealing the structural background of physiological processes that modulate and govern the operation of paraventricular neurons.

Animal models for osmoregulatory disturbances.

For the various types of di in humans, animal models are available. However, their value for explaining human di is for the major part an indirect one; by studying cellular mechanisms in these animal models, fundamental aspects of the cellular processes become available, which will help to understand similar processes in human di and subsequently lead to the molecular cause(s) of the various types of human di. Finally, it is to be expected that in the very near future transgenic animals will be raised in which very specific genetic information is overexpressed (or knocked out by homologous recombination; McMahon and Bradley, 1990). Recently hypervasopressinemia could be shown in transgenic mice, providing an animal model for the syndrome of the inappropriate VP secretion (Bartter and Schwartz, 1967), which is often observed in patients with lung cancers that ectopically express the VP gene (Habener et al., 1989). Furthermore it will be possible to study the exact cause(s) of human di by performing in vitro mutagenesis and to express the RNA constructs within a cell-free translation system and in oocytes (e.g., Schmale et al., 1989) and subsequently study the pattern of precursor synthesis, packaging and processing.