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Hyponatremia is the most common clinical electrolyte disorder. Chronic hyponatremia has been recently reported to be associated with falls, fracture, osteoporosis, neurocognitive impairment, and mental manifestations. In the treatment of chronic hyponatremia, overly rapid correction of hyponatremia can cause osmotic demyelination syndrome (ODS), a central demyelinating disease that is also associated with neurological morbidity and mortality. Using a rat model, we have previously shown that microglia play a critical role in the pathogenesis of ODS. However, the direct effect of rapid correction of hyponatremia on microglia is unknown. Furthermore, the effect of chronic hyponatremia on microglia remains elusive. Using microglial cell lines BV-2 and 6-3, we show here that low extracellular sodium concentrations (36 mmol/L decrease; LS) suppress Nos2 mRNA expression and nitric oxide (NO) production of microglia. On rapid correction of low sodium concentrations, NO production was significantly increased in both cells, suggesting that acute correction of hyponatremia partly directly contributes to increased Nos2 mRNA expression and NO release in ODS pathophysiology. LS also suppressed expression and nuclear translocation of nuclear factor of activated T cells-5 (NFAT5), a transcription factor that regulates the expression of genes involved in osmotic stress. Furthermore, overexpression of NFAT5 significantly increased Nos2 mRNA expression and NO production in BV-2 cells. Expressions of Nos2 and Nfat5 mRNA were also modulated in microglia isolated from cerebral cortex in chronic hyponatremia model mice. These data indicate that LS modulates microglial NO production dependent on NFAT5 and suggest that microglia contribute to hyponatremia-induced neuronal dysfunctions., Competing Interests: Declaration of competing interest The authors have nothing to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

A 74-year-old woman's persistent hyponatraemia led to the discovery of an adenosquamous carcinoma within an intrapulmonary bronchogenic cyst (IPBC), diagnosed 59 years prior. This is the first reported case of such a transformation in an IPBC. An adenosquamous carcinoma, originating from an intrapulmonary bronchogenic cyst identified 59 years prior, was discovered during the workup for a patient's unexplained, persistent hyponatraemia., (© 2024 The Author(s). Cytopathology published by John Wiley & Sons Ltd.)

Carbamoyl phosphate synthetase 1 (CPS1) is the most abundant hepatocyte mitochondrial matrix protein. Hypoosmotic stress increases CPS1 release in isolated mouse hepatocytes without cell death. We hypothesized that increased CPS1 release during hypoosmosis is selective and associates with altered mitochondrial morphology. Both ex vivo and in vivo models were assessed. Mouse hepatocytes and livers were challenged with isotonic or hypoosmotic (35 mosM) buffer. Mice were injected intraperitoneally with water (10% body weight) with or without an antidiuretic. Mitochondrial and cytosolic fractions were isolated using differential centrifugation, then analyzed by immunoblotting to assess subcellular redistribution of four mitochondrial proteins: CPS1, ornithine transcarbamylase (OTC), pyrroline-5-carboxylate reductase 1 (PYCR1), and cytochrome c. Mitochondrial morphology alterations were examined using electron microscopy. Hypoosmotic treatment of whole livers or hepatocytes led to preferential or increased mitochondrial release, respectively, of CPS1 as compared with two mitochondrial matrix proteins (OTC/PYCR1) and with the intermembrane space protein, cytochrome c. Mitochondrial apoptosis-induced channel opening using staurosporine in hepatocytes led to preferential CPS1 and cytochrome c release. The CPS1-selective changes were accompanied by dramatic alterations in ultrastructural mitochondrial morphology. In mice, hypoosmosis/hyponatremia led to increased liver vascular congestion and increased CPS1 in bile but not blood, coupled with mitochondrial structural alterations. In contrast, isotonic increase of intravascular volume led to a decrease in mitochondrial size with limited change in bile CPS1 compared with hypoosmotic conditions and absence of the hypoosmosis-associated histological alterations. Taken together, hepatocyte CPS1 is selectively released in response to hypoosmosis/hyponatremia and provides a unique biomarker of mitochondrial injury. NEW & NOTEWORTHY Exposure of isolated mouse livers, primary cultured hepatocytes, or mice to hypoosmosis/hyponatremia conditions induces significant mitochondrial shape alterations accompanied by preferential release of the mitochondrial matrix protein CPS1, a urea cycle enzyme. In contrast, the intermembrane space protein, cytochrome c, and two other matrix proteins, including the urea cycle enzyme ornithine transcarbamylase, remain preferentially retained in mitochondria. Therefore, hepatocyte CPS1 manifests unique mitochondrial stress response compartmentalization and is a sensitive sensor of mitochondrial hypoosmotic/hyponatremic injury.

Dilutional hyponatremia due to increased plasma arginine vasopressin (AVP) is associated with liver cirrhosis. However, plasma AVP remains elevated despite progressive hypoosmolality. This study investigated changes to inhibitory control of supraoptic nucleus (SON) AVP neurons during liver cirrhosis. Experiments were conducted with adult male Sprague-Dawley rats. Bile duct ligation was used as a model of chronic liver cirrhosis. An adeno-associated virus containing a construct with an AVP promoter and either green fluorescent protein (GFP) or a ratiometric chloride indicator, ClopHensorN, was bilaterally injected into the SON of rats. After 2 weeks, rats received either BDL or sham surgery, and liver cirrhosis was allowed to develop for 4 weeks. In vitro, loose patch recordings of action potentials were obtained from GFP-labeled and unlabeled SON neurons in response to a brief focal application of the GABA A agonist muscimol (100 μM). Changes to intracellular chloride ([Cl]i) following muscimol application were determined by changes to the fluorescence ratio of ClopHensorN. The contribution of cation chloride cotransporters NKCC1 and KCC2 to changes in intracellular chloride was investigated using their respective antagonists, bumetanide (BU, 10 μM) and VU0240551 (10 μM). Plasma osmolality and hematocrit were measured as a marker of dilutional hyponatremia. The results showed reduced or absent GABA A -mediated inhibition in a greater proportion of AVP neurons from BDL rats as compared to sham rats (100% inhibition in sham vs. 47% in BDL, p = .001). Muscimol application was associated with increased [Cl]i in most cells from BDL as compared to cells from sham rats (χ 2  = 30.24, p < .001). NKCC1 contributed to the impaired inhibition observed in BDL rats (p < .001 BDL - BU vs. BDL + BU). The results show that impaired inhibition of SON AVP neurons and increased intracellular chloride contribute to the sustained dilutional hyponatremia in liver cirrhosis., (© 2023 The Authors. Journal of Neuroendocrinology published by John Wiley & Sons Ltd on behalf of British Society for Neuroendocrinology.)

Abstract: Central pontine myelinolysis is most commonly associated with rapid correction of hyponatremia and has historically been associated with alcoholism. In this case report, 2 deaths with gross findings of central pontine lesions led to the possibility that CPM may have been a potential mechanism of death. Subsequent analysis revealed that these lesions were incidental findings. This case report discusses the importance of appropriate microscopic and immunohistochemical analysis of suspected CPM cases., Competing Interests: The authors report no conflict of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Gitelman and Bartter syndromes are rare inherited diseases that belong to the category of renal tubulopathies. The genes associated with these pathologies encode electrolyte transport proteins located in the nephron, particularly in the Distal Convoluted Tubule and Ascending Loop of Henle. Therefore, both syndromes are characterized by alterations in the secretion and reabsorption processes that occur in these regions. Patients suffer from deficiencies in the concentration of electrolytes in the blood and urine, which leads to different systemic consequences related to these salt-wasting processes. The main clinical features of both syndromes are hypokalemia, hypochloremia, metabolic alkalosis, hyperreninemia and hyperaldosteronism. Despite having a different molecular etiology, Gitelman and Bartter syndromes share a relevant number of clinical symptoms, and they have similar therapeutic approaches. The main basis of their treatment consists of electrolytes supplements accompanied by dietary changes. Specifically for Bartter syndrome, the use of non-steroidal anti-inflammatory drugs is also strongly supported. This review aims to address the latest diagnostic challenges and therapeutic approaches, as well as relevant recent research on the biology of the proteins involved in disease. Finally, we highlight several objectives to continue advancing in the characterization of both etiologies.

Context: In patients with cancer, hyponatremia is associated with increased morbidity and mortality and can delay systemic therapy., Objective: To assess the safety and efficacy of low-dose tolvaptan (7.5 mg) for hospitalized, adult patients with hyponatremia due to syndrome of inappropriate antidiuresis (SIAD), and coexisting malignancy., Methods: Retrospective evaluation in a tertiary cancer center., Results: Fifty-five patients with mean baseline serum sodium (sNa) 117.9 ± 4.6 mmol/L were included. In total, 90.9% had severe hyponatremia (sNa < 125 mmol/L). Mean age was 65.1 ± 9.3 years. Following an initial dose of tolvaptan 7.5 mg, median (range) increase in sNa observed at 24 hours was 9 (1-19) mmol/L. Within 1 week, 39 patients (70.9%) reached sNa ≥ 130 mmol/L and 48 (87.3%) had sNa rise of ≥5 mmol/L within 48 hours. No severe adverse events were reported. Thirty-three (60%) and 17 (30.9%) patients experienced sNa rise of ≥8 and ≥12 mmol/L/24 hours, respectively. The rate of sNa correction in the first 24 hours was significantly higher among participants that continued fluid restriction after tolvaptan administration (median [quantiles]: 14 [9-16] versus 8 [5-11] mmol/L, P = .036). Moreover, in the over-rapid correction cohort (≥12 mmol/L/24 hours) demeclocycline was appropriately discontinued only in 60% compared with 91.7% of the remaining participants (P = .047). Lower creatinine was predictive of higher sNa correction rate within 24 hours (P = .01)., Conclusion: In the largest series to date, although low-dose tolvaptan was demonstrated to be effective in correcting hyponatremia due to SIAD in cancer patients, a significant proportion experienced over-rapid correction. Concurrent administration of demeclocycline and/or fluid restriction must be avoided due to the increased risk of over-rapid correction., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Dysnatremia and dyskalemia are common problems in acutely hospitalized elderly patients. These disorders are associated with an increased risk of mortality and functional complications that often occur concomitantly with acute kidney injury in addition to multiple comorbidities. In a single-center prospective observational study, we recruited 401 acute geriatric inpatients. In-hospital outcomes included all-cause mortality, length of stay, and changes in functional status as determined by the Activities of Daily Living (ADL) scale, Eastern Cooperative Oncology Group (ECOG) performance, and Clinical Frailty Scale (CFS). The prevalence of dysnatremia alone, dyskalemia alone, and dysnatremia plus dyskalemia during initial hospitalization were 28.4%, 14.7% and 32.4%, respectively. Patients with electrolyte imbalance exhibited higher mortality rates and longer hospital stays than those without electrolyte imbalance. Those with initial dysnatremia, or dysnatremia plus dyskalemia were associated with worse ADL scores, ECOG performance and CFS scores at discharge. Subgroup analyses showed that resolution of dysnatremia was related to reduced mortality risk and improved CFS score, whereas recovery of renal function was associated with decreased mortality and better ECOG and CFS ratings. Our data suggest that restoration of initial dysnatremia and acute kidney injury during acute geriatric care may benefit in-hospital survival and functional status at discharge., (© 2021. The Author(s).)

COVID-19 has changed the nature of medical consultations, emphasizing virtual patient counselling, with relevance for patients with diabetes insipidus (DI) or hyponatraemia. The main complication of desmopressin treatment in DI is dilutional hyponatraemia. Since plasma sodium monitoring is not always possible in times of COVID-19, we recommend to delay the desmopressin dose once a week until aquaresis occurs allowing excess retained water to be excreted. Patients should measure their body weight daily. Patients with DI admitted to the hospital with COVID-19 have a high risk for mortality due to volume depletion. Specialists must supervise fluid replacement and dosing of desmopressin. Patients after pituitary surgery should drink to thirst and measure their body weight daily to early recognize the development of postoperative SIAD. They should know hyponatraemia symptoms. Hyponatraemia in COVID-19 is common with a prevalence of 20-30% and is mostly due to SIAD or hypovolaemia. It mirrors disease severity and is an early predictor of mortality. Hypernatraemia may also develop in COVID-19 patients, with a prevalence of 3-5%, especially in ICU, and derives from different multifactorial reasons, for example, due to insensible water losses from pyrexia, increased respiration rate and use of diuretics. Hypernatraemic dehydration may contribute to the high risk of acute kidney injury in COVID-19. IV fluid replacement should be administered with caution in severe cases of COVID-19 because of the risk of pulmonary oedema.

Objective: Treatment of symptomatic hyponatremia is not well established. The European guidelines recommend bolus-wise administration of 150 mL of 3% hypertonic saline. This recommendation is, however, based on low level of evidence., Design: Observational study., Methods: Sixty-two consecutive hyponatremic patients admitted to the emergency department or intensive care unit of the University Hospital Wuerzburg were divided in subgroups according to treatment (150 mL bolus of 3% hypertonic saline or conventional treatment) and symptom severity. Treatment target was defined as an increase in serum sodium by 5-10 mEq/L within first 24 h and maximum 8 mEq/L during subsequent 24 h., Results: Thirty-three out of sixty-two patients (53%) were presented with moderate symptoms and 29/62 (47%) with severe symptoms. Thirty-six were treated with hypertonic saline and 26 conventionally. In the hypertonic saline group, serum sodium increased from 116 ± 7 to 123 ± 6 (24 h) and 127 ± 6 mEq/L (48 h) and from 121 ± 6 to 126 ± 5 and 129 ± 4 mEq/L in the conventional group, respectively. Overcorrection at 24 h occurred more frequent in patients with severe symptoms than with moderate symptoms (38% vs 6%, P < 0.05). Diuresis correlated positively with the degree of sodium overcorrection at 24 h (r = 0.6, P < 0.01). Conventional therapies exposed patients to higher degrees of sodium fluctuations and an increased risk for insufficient sodium correction at 24 h compared to hypertonic saline (RR: 2.8, 95% CI: 1.4-5.5)., Conclusion: Sodium increase was more constant with hypertonic saline, but overcorrection rate was high, especially in severely symptomatic patients. Reducing bolus-volume and reevaluation before repeating bolus infusion might prevent overcorrection. Symptoms caused by hypovolemia can be misinterpreted as severely symptomatic hyponatremia and diuresis should be monitored.

Aldosterone synthase deficiency (ASD) is a rare potentially life-threatening genetic disorder that usually presents during infancy due to pathogenic variants in the CYP11B2 gene. Knowledge about CYP11B2 variants in the Arab population is scarce. Here, we present and analyze five Palestinian patients and their different novel pathogenic variants. Data on clinical presentation, electrolytes, plasma renin activity, and steroid hormone levels of five patients diagnosed with ASD were summarized. Sequencing of the CYP11B2 gene exons was followed by evolutionary conservation analysis and structural modeling of the variants. All patients were from highly consanguineous Palestinian families. The patients presented at 1-4 months of age with recurrent vomiting, poor weight gain, hyponatremia, hyperkalemia, and low aldosterone levels. Genetic analysis of the CYP11B2 gene revealed three homozygous pathogenic variants: p.Ser344Profs*9, p.G452W in two patients from an extended family, and p.Q338stop. A previously described pathogenic variant was found in one patient: p.G288S. We described four different CYP11B2 gene pathogenic variants in a relatively small population. Our findings may contribute to the future early diagnosis and therapy for patients with ASD among Arab patients who present with failure to thrive and compatible electrolyte disturbances., (© 2021 Wiley Periodicals LLC.)

Apelin and arginine-vasopressin (AVP) are conversely regulated by osmotic stimuli. We therefore hypothesized that activating the apelin receptor (apelin-R) with LIT01-196, a metabolically stable apelin-17 analog, may be beneficial for treating the Syndrome of Inappropriate Antidiuresis, in which AVP hypersecretion leads to hyponatremia. We show that LIT01-196, which behaves as a potent full agonist for the apelin-R, has an in vivo half-life of 156 minutes in the bloodstream after subcutaneous administration in control rats. In collecting ducts, LIT01-196 decreases dDAVP-induced cAMP production and apical cell surface expression of phosphorylated aquaporin 2 via AVP type 2 receptors, leading to an increase in aqueous diuresis. In a rat experimental model of AVP-induced hyponatremia, LIT01-196 subcutaneously administered blocks the antidiuretic effect of AVP and the AVP-induced increase in urinary osmolality and induces a progressive improvement of hyponatremia. Our data suggest that apelin-R activation constitutes an original approach for hyponatremia treatment.

Only a few cases of syndrome of inappropriate antidiuretic hormone secretion (SIADH) in the setting of amyotrophic lateral sclerosis (ALS) have been described in the literature. We present the case of an 81-year-old male who developed severe hyponatremia following elective total hip replacement. His past medical history included prostate cancer, which was under surveillance, and ischemic heart disease. He reported recent weight loss, worsening shortness of breath, and lethargy. SIADH was diagnosed on the basis of hyponatremia, elevated urinary sodium, and decreased serum osmolality, presumed secondary to surgery. Investigations revealed no occult malignancy and no other cause for hyponatremia. He was discharged when sodium levels had normalized, however, he then had several further admissions for hyponatremia, general fatigue, and breathlessness. His condition continued to decline, and he developed dysphagia, weakness, and tongue fasciculations. Neurological examination showed globally decreased power, increased tone, and fasciculations. MRI of the brain was normal. He did not respond to neostigmine treatment, and a presumed diagnosis of motor neuron disease was made. The patient passed away shortly after this, and a post-mortem confirmed the diagnosis of ALS. Drug, post-operative, and cancer-related causes were precluded by the timing of onset of hyponatremia. We present this case and an analysis of previously published cases alongside a discussion on the potential causative mechanisms.

There is concern that the global burden of coronavirus disease of 2019 (COVID-19) due to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection might yield an increased occurrence of Guillain-Barré syndrome (GBS). It is currently unknown whether concomitant SARS-CoV-2 infection and GBS are pathophysiologically related, what biomarkers are useful for diagnosis, and what is the optimal treatment given the medical comorbidities, complications, and simultaneous infection. We report a patient who developed severe GBS following SARS-CoV-2 infection at the peak of the initial COVID-19 surge (April 2020) in New York City and discuss diagnostic and management issues and complications that may warrant special consideration in similar patients.

Objective: Pleurex catheters are a form of palliative therapy for patients, offering relief from symptomatic ascites while also affording greater independence and flexibility; however, aggressive drainage can lead to significant total body sodium losses. We describe the course of patients with "Pleurex desalination," an under-appreciated cause of hypovolemic hyponatremia, highlighting its unique pathophysiology and providing recommendations on how to manage these complex patients., Patients and Methods: We included representative patients with "Pleurex desalination" who were evaluated and treated by the renal consult service at Brigham and Women's between 2017 and 2019., Results: We identified 3 patients who were hospitalized with "Pleurex desalination" and had complete data on serum and urine studies, as well as treatment course. We demonstrate that patients with "Pleurex desalination" were removing up to 1 to 2 L of ascitic fluid a day and were admitted with signs and symptoms of profound hypovolemia and hyponatremia. Patients worsened with administration of diuretics and salt restriction and improved with aggressive fluid resuscitation in the form of hypertonic saline, normal saline, and/or intravenous albumin., Conclusion: "Pleurex desalination" is an under-recognized cause of hyponatremia; at-risk patients require close observation and periodic resuscitation with intravenous, volume-expanding fluids.

Background: Elevated neutrophil-lymphocyte ratio (NLR) and hyponatremia each predict poor prognosis in renal cell carcinoma (RCC). Since no previous studies have looked at the combined effect of these two prognostic markers, we examined how NLR and hyponatremia combined associates with mortality and hypothesized that elevated NLR and hyponatremia at RCC diagnosis and at RCC recurrence indicate poorer prognosis. Material and methods: Using Danish medical registries 1999-2015, we included 970 patients from two regions with incident RCC and a measurement of NLR and sodium. NLR was categorized as ≤3.0 and >3.0 and sodium as < lower limit of normal (LLN) and ≥ LLN. Outcomes were survival after RCC diagnosis and first recurrence, respectively. We estimated absolute survival and hazard ratios (HR) using multivariate Cox regression. Results: At RCC diagnosis, 559 (57.6%) had NLR >3.0 and 240 (24.7%) had hyponatremia, the 5 year-survival rate was 35.2% in NLR > 3.0 vs. 69.2% in NLR ≤3.0, adjusted HR 1.8 (95% confidence intervals (CI), 1.4; 2.2). In patients with NLR >3.0 and concomitant hyponatremia vs. NLR ≤3.0 and normal sodium the 5-year survival rate was 21.7% vs. 73.2%, adjusted HR 2.8 (95% CI, 2.1; 3.8). At RCC recurrence, patients with NLR >3.0 and hyponatremia similarly had poorest survival, adjusted HR 3.6 (95% CI, 1.0; 12.8). Conclusion : Elevated NLR alone and in combination with hyponatremia at time of initial RCC diagnosis and at time of RCC recurrence are associated with poor prognosis. Combining these two prognostic markers yield a stronger association than NLR considered alone. This may impact prognostic prediction and its related therapeutic strategy.

Hyponatremia due to elevated arginine vasopressin (AVP) secretion increases mortality in liver failure patients. The mechanisms causing dysregulation of AVP secretion are unknown. Our hypothesis is that inappropriate AVP release associated with liver failure is due to increased brain-derived neurotrophic factor (BDNF) in the supraoptic nucleus (SON). BDNF diminishes GABAA inhibition in SON AVP neurons by increasing intracellular chloride through tyrosine receptor kinase B (TrkB) activation and downregulation of K+/Cl- cotransporter 2 (KCC2). This loss of inhibition could increase AVP secretion. This hypothesis was tested using shRNA against BDNF (shBDNF) in the SON in bile duct ligated (BDL) male rats. All BDL rats had significantly increased liver weight (p < 0.05; 6-9) compared to shams. BDL rats with control -shRNA injections (BDL scrambled [SCR]) developed hyponatremia with increased plasma AVP and copeptin (CPP; all p < 0.05; 6-9) compared to sham groups. This is the first study to show that phosphorylation of TrkB is significantly increased along with significant decrease in phosphorylation of KCC2 in BDL SCR rats compared to the sham rats (p < 0.05;6-8). Knockdown of BDNF in the SON of BDL rats (BDL shBDNF) significantly increased plasma osmolality and hematocrit compared to BDL SCR rats (p < 0.05; 6-9). The BDL shBDNF rats had significant (p < 0.05; 6-9) decreases in plasma AVP and CPP concentration compared to BDL SCR rats. The BDNF knockdown also significantly blocked the increase in TrkB phosphorylation and decrease in KCC2 phosphorylation (p < 0.05; 6-8). The results indicate that BDNF produced in the SON contributes to increased AVP secretion and hyponatremia during liver failure., (© 2019 The Author(s) Published by S. Karger AG, Basel.)

Introduction: Hyponatraemia is one of the most frequent laboratory findings in hospitalised patients. We present an unusual case of hyponatraemia in a 23-year-old female secondary to acute intermittent porphyria (AIP), a rare inborn error of metabolism., Case Report: The patient presented with upper respiratory tract infection, fever, seizures and abdominal pain. An initial diagnosis of encephalitis was made. In view of the unexplained abdominal pain with other clinical findings such as posterior reversible encephalopathy syndrome by CT brain, temporary blindness as well as hyponatraemia, acute intermittent porphyria was suspected. Urine delta aminolaevulinic acid (δ-ALA) and porphobilinogen were elevated confirming the diagnosis of AIP. Genetic studies were done for this patient. The patient had a complete resolution of her symptoms with carbohydrate loading and high caloric diet., Conclusion: Although rare, AIP should be considered as a cause of hyponatraemia in a patient who presents with signs and/or symptoms that are characteristic of this disease.

KLHL40-related nemaline myopathy is a severe autosomal recessive muscle disorder. The current study describes 4 cases of KLHL40-related nemaline myopathy in Hong Kong ethnic Chinese presenting within 3 years, which are confirmed with clinicopathologic features and genetic studies. The incidence is estimated to be at least 1 in 45 226 livebirths (at least 1 in 41 608 among ethnic Chinese livebirths) in Hong Kong. Hyponatremia appears to be another common feature in these patients. Salient histological features include nemaline bodies ranging from 200 to 500 nm in diameters on ultrastructural examination as well as negative KLHL40 immunohistochemistry; type II fiber predominance is obvious in 2 cases. We demonstrate the founder effect associated with genetic variant c.1516A>C (p.Thr506Pro) by polymorphic marker analysis, which revealed a 0.56-0.75-Mb or 0.41-0.78-cM shared haplotype encompassing the disease allele. The mutation is believed to have occurred around 412 generations ago or 6220 BCE, as estimated using DMLE+ and a formula described by Boehnke. We believe the founder variant might possibly underlie a sizable portion of nemaline myopathy in ethnic Chinese. Analysis of the KLHL40 gene may be considered as the first-tier testing of congenital myopathy in this ethnic group., (© 2019 American Association of Neuropathologists, Inc. All rights reserved.)

A murine model used to investigate the osmotic demyelination syndrome (ODS) demonstrated ultrastructural damages in thalamus nuclei. Following chronic hyponatremia, significant myelinolysis was merely detected 48 h after the rapid reinstatement of normonatremia (ODS 48 h). In ODS samples, oligodendrocytes and astrocytes revealed injurious changes associated with a few cell deaths while both cell types seemed to endure a sort of survival strategy: (a) ODS 12 h oligodendrocytes displayed nucleoplasm with huge heterochromatic compaction, mitochondria hypertrophy, and most reclaimed an active NN cell aspect at ODS 48 h. (b) Astrocytes responded to the osmotic stress by overall cell shrinkage with clasmatodendrosis, these changes accompanied nucleus wrinkling, compacted and segregated nucleolus, destabilization of astrocyte-oligodendrocyte junctions, loss of typical GFAP filaments, and detection of round to oblong woolly, proteinaceous aggregates. ODS 48 h astrocytes regained an active nucleus aspect, without restituting GFAP filaments and still contained cytoplasmic proteinaceous deposits. (c) Sustaining minor shrinking defects at ODS 12 h, neurons showed slight axonal injury. At ODS 48 h, neuron cell bodies emerged again with deeply indented nucleus and, owing nucleolus translational activation, huge amounts of polysomes along with secretory-like activities. (d) In ODS, activated microglial cells got stuffed with huge lysosome bodies out of captures cell damages, leaving voids in interfascicular and sub-vascular neuropil. Following chronic hyponatremia, the murine thalamus restoration showed macroglial cells acutely turned off transcriptional and translational activities during ODS and progressively recovered activities, unless severely damaged cells underwent cell death, leading to neuropil disruption and demyelination.

Inappropriate antidiuretic hormone syndrome (SIADH) may develop after intracranial surgery. SIADH in the pediatric age group is usually encountered in patients with an intracranial mass both before and after surgery. Fluid restriction is the standard therapy in SIADH. However, a resistant, hyponatremic pattern may be encountered in some cases. Vaptans have been recently introduced for treatment of hyponatremia due to SIADH. There is inadequate data concerning tolvaptan treatment in pediatric patients. We present a 13 year-old female with SIADH of triphasic episode who was transferred to our clinic after surgery for craniopharyngioma. Resistant hyponatremia did not resolve despite fluid restriction and hypertonic saline support. The patient responded rapidly to a single dose of tolvaptan, with no adverse effect, which resulted in successful control of her SIADH.

Background: A consistent percentage of patients with metastatic non-small cell lung cancer (NSCLC) derives no or only marginal benefit from immunotherapy (IO)., Objective: Since serum sodium has been linked to both prognosis in NSCLC and modulation of immune cells activity, we aimed to assess the association between low baseline serum sodium concentration (≤ 135 mEq/L) and clinical outcomes of patients with metastatic NSCLC treated with IO., Patients and Methods: We included metastatic NSCLC patients treated with checkpoint inhibitors in our department from April 2013 to April 2018 with available baseline serum sodium concentration. Demographics, clinical and pathological characteristics were collected. Survival analyses were performed using the Kaplan-Meier method and the Cox proportional-hazards model., Results: Of 197 patients included, 26 (13%) presented low baseline serum sodium concentration. Patients in the low sodium cohort experienced a poorer disease control rate (OR 0.36; 95% CI, 0.15-0.86; Wald test P = .02), median overall survival (OS) (2.8 vs. 11.6 months; HR 3.00; 95% CI, 1.80-4.80; P < .001) and progression-free survival (PFS) (1.8 vs. 3.3 months; HR 2.60; 95% CI, 1.70-3.90; P < .001) compared to patients in the control cohort. At multivariate analyses, low baseline serum sodium concentration was independently associated with disease control and OS, but not with PFS., Conclusions: Our study showed for the first time that low baseline serum sodium concentration is associated with impaired clinical outcomes in patients with metastatic NSCLC treated with IO. The role of serum sodium concentration in this setting warrants further pre-clinical and clinical investigation.

Cerebral edema leading to elevated intracranial pressure (ICP) is a fundamental concern after severe traumatic brain injury (TBI), stroke, and severe acute hyponatremia. We describe a swine model of water intoxication and its cerebral histological and physiological sequela. We studied female swine weighing 35-45 kg. Four serum sodium intervals were designated: baseline, mild, moderate, and severe hyponatremia attained by infusing hypotonic saline. Intracranial fluid injections were performed to assess intracranial compliance. At baseline and following water intoxication wedge biopsy was obtained for pathological examination and electron microscopy. We studied 8 swine and found an increase in ICP that was strongly related to the decrease in serum sodium level. Mean ICP rose from a baseline of 6 ± 2 to 28 ± 6 mm Hg during severe hyponatremia, while cerebral perfusion pressure (CPP) decreased from 72 ± 10 to 46 ± 11 mm Hg. Brain tissue oxygen tension (PbtO 2 ) decreased from 18.4 ± 8.9 to 5.3 ± 3.0 mm Hg. Electron microscopy demonstrated intracellular edema and astrocytic foot process swelling following water intoxication. With severe hyponatremia, 2 cc intracranial fluid injection resulted in progressively greater ICP dose, indicating a worsening intracranial compliance. Our model leads to graded and sustained elevation of ICP, lower CPP, and decreased PbtO 2 , all of which cross clinically relevant thresholds. Intracranial compliance worsens with increased cerebral swelling. This model may serve as a platform to study which therapeutic interventions best improve the cerebral physiological profile in the face of severe brain edema., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Hyponatremia is a commonly observed complication that is related to hypoalbuminemia and portal hypertension in patients with advanced liver cirrhosis. Hyponatremia in patients with liver cirrhosis is mostly dilutional hyponatremia and is defined when the serum sodium concentration is below 130 meq/L. The risk of complications increases significantly in cirrhotic patients with hyponatremia, which includes spontaneous bacterial peritonitis, hepatorenal syndrome, and hepatic encephalopathy. In addition, hyponatremia is associated with increased morbidity and mortality in patients with cirrhosis, and is an important prognostic factor before and after liver transplantation. The conventional therapies of hyponatremia are albumin infusion, fluid restriction and loop diuretics, but these are frequently ineffective. This review investigates the pathophysiology and various therapeutic modalities, including selective vasopressin receptor antagonists, for the management of hyponatremia in patients with liver cirrhosis.

The case of a 58-year old female patient with epidermal growth factor-positive pulmonary adenocarcinoma treated with the tyrosine kinase inhibitor afatinib is reported. After several months of first-line therapy the patient developed severe hyponatremia and tumor reassessment revealed a progressive course of the lung cancer. Rebiopsy showed transformation of the tumor into small-cell lung cancer. Therapy with afatinib was stopped immediately and platin-based chemotherapy was started. This case shows that tumor transformation under tyrosine kinase inhibitor therapy from non-small-cell into small-cell lung cancer can occur in rare cases.

Hyponatremia is relevant to heart failure, liver cirrhosis and stroke, but the prognostic value of serum sodium levels in patients with acute coronary syndrome are still unclear. So we did a systematic review and meta-analysis to assess the prognostic value of hyponatremia on adverse events in patients after ACS. We systematically searched PubMed, Embase and Cochrane Library to find literatures which studied the prognostic value of hyponatremia in patients with ACS. Our main endpoints were the all-cause mortality and heart failure in the short- and long-term. Of 369 identified studies, 20 studies were included in our analysis. Compared with the normal natrium, hyponatremia was significantly associated with the increased risks of all-cause mortality within 30 days (RR: 2.18; 95%CI: 1.96-2.42) and during the follow-ups (HR: 1.74; 95%CI: 1.56-1.942). For the second endpoint of short- and long-term heart failure, the pooled effect sizes in hyponatremia patients were 1.72(95%CI: 1.38-2.14) and 1.69(95%CI: 1.12-2.55) respectively. In conclusion, hyponatremia has a significant prognostic value for short- and long-term adverse event in patients after ACS, the dynamic monitoring of serum sodium levels may could help physicians to identify high risk ACS patients and to stratify risk for optimal management.

Idiopathic Edema (IE), is a syndrome involving real or perceived weight gain secondary to the pathological retention of fluid. This syndrome of generalized edema is almost solely reported in women. The diagnosis of IE is one of exclusion and requires a careful history, physical exam, and clinical suspicion. The aim of this article is to provide a comprehensive review of the available literature in order to attempt to define IE, identify the possible causes, review the proposed pathophysiology, and discuss potential treatment options., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective: To summarize and analyze the clinical features and etiologies in hospitalized patients with syndrome of inappropriate antidiuretics (SIAD) during the past 25 years. Methods: All data of 128 patients with SIAD admitted to Chinese PLA General Hospital since January 1991 to January 2016 were collected. SIAD was diagnosed based on the 1957 criterion. Results: (1) The most frequent causes of increased inappropriate secretion of vasopressin were malignant tumors, lung diseases (e. g. pneumonia), and central nervous system diseases, in which malignant tumors accounted for 38.28% of the SIAD. (2) During the past 25 years, the proportion of malignant diseases declined from 4/7 to 35.29%, while, the proportion of pulmonary infection increased from 1/7 to 35.29% ( P <0.05). (3) The patients with malignant tumors had the lowest serum sodium and serum osmolality among all SIAD patients. (4) CT scan had a high diagnostic value for chest and brain detection. (5) Among three SIAD subjects with unknown reasons at onset, two were diagnosed with small cell lung cancer and one with gastric cancer during follow-up. Conclusion: The etiology of SIAD is complex and it could be attributed to multifarious etiological factors. Malignant tumors account for the largest proportion of all patients, and pulmonary infection was ranked in second place. Cautions on tumors have to be taken when serum sodium of a SIAD patient is below 118.1 mmol/L.

Introduction: Dysnatremia commonly occur in the intensive care unit (ICU) management of patients with aneurysmal subarachnoid hemorrhage (SAH). However, detailed management strategies have not been provided even by current guidelines. The purposes of this study were to examine the association of abnormal serum sodium levels with unfavorable neurologic outcomes and to identify the target range of serum sodium in patients with SAH., Methods: We retrospectively reviewed all patients who were consecutively hospitalized with a confirmed diagnosis of SAH between January 2009 and December 2015. Univariate/multivariate analyses were performed to identify the independent predictors of an unfavorable neurologic outcome (modified Rankin scale of 3-6 upon hospital discharge)., Results: There were 131 patients included in this study. Unfavorable neurologic outcomes occurred in 45% of patients. On multiple regression analysis, age, Hunt and Kosnik grade, and serum sodium levels in the ICU at the maximum [odds ratio (OR), 1.18; 95% CI, 1.05-1.35; P < 0.01] and minimum (OR, 0.88; 95% CI, 0.77-0.99; P = 0.048) values were significantly associated with unfavorable neurologic outcomes. The receiver operating characteristic curve analysis showed that the cut-off serum sodium levels were 145 mmol/L for maximum value and 132 mmol/L for minimum value. Patients with hyponatremia and hypernatremia during the first 2 weeks in the ICU accounted for 88.2% of patients with an unfavorable neurologic outcome; whereas, those with normal sodium levels accounted for only 15.6%., Conclusions: In patients with SAH, both hyponatremia and hypernatremia during ICU management were significantly associated with unfavorable neurologic outcomes.

Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m 2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m 2 The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m 2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m 2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892., (© 2017 by The American Society of Hematology.)

Hyponatremia is the most common electrolyte disorder and also a predictor of mild cognition impairment. However, the association between hyponatremia and dementia in long follow up periods is rarely investigated. A retrospective cohort study was performed using the claims data of all insured residents who were covered by Taiwan's universal health insurance from 2000 to 2011. A total of 4900 hyponatremia patients and 19545 matched comparisons were recruited for the analysis. The incidences of hyponatremia and dementia were diagnosed with clinical protocol and defined using the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Cox proportional hazard regression and Kaplan-Meier curves were used for the analyses. Independent of adjusting factors, hyponatremia patients had 2.36-fold higher chances of suffering dementia, including Alzheimer's disease (AD) and non-AD dementia, than the comparisons. Severe hyponatremia patients had higher risks of suffering dementia than the non-severe hyponatremia patients (adjusted hazard ratio: 4.29 (95% CI: 3.47-5.31) versus 2.08 (95% CI: 1.83-2.37)). A dose response relationship was observed between hyponatremia and dementia. Those hyponatremia patients with baseline or incident stroke had significantly higher chances of suffering dementia compared with those patients without hyponatremia and stroke. Stroke is a significant modifier of the relationship between hyponatremia and dementia. Cerebrovascular disease after incident hyponatremia must be prevented to reduce the incidence of dementia.

Background: Craniopharyngiomas are rare intracranial tumors commonly presenting with neurological symptoms. Reports of severe hyponatremia as a presenting manifestation of a craniopharyngioma and hyponatremia-induced myopathy are rare. We report the case of a patient with craniopharyngioma presenting with severe hyponatremia, panhypopituitarism, and hyponatremia-induced myopathy., Case Presentation: A 52-year-old Sri Lankan man presented with anorexia, nausea, fatigue, generalized muscle weakness, and cramps for 1 week. The onset of his illness had been preceded by vomiting and diarrhea for 1 day which he attributed to food poisoning. On examination, he had an apathetic disposition with a generalized "sallow complexion." He was not dehydrated. Apart from reduced muscle power (4/5) and hyporeflexia, the neurological examination was normal. His serum sodium was 102 mmol/l; potassium 4.1 mmol/l; chloride 63 mmol/l; plasma osmolality 272 mosm/KgH 2 O; urine osmolality 642 mosm/KgH 2 O; and urine sodium 79 mmol/l. His creatine phosphokinase was 12,400 U/l, lactate dehydrogenase 628 U/l, aspartate aminotransferase 360 U/l, and alanine aminotransferase 64 U/l. His hormone profile revealed panhypopituitarism. An electromyogram showed nonspecific abnormalities while a muscle biopsy did not show any pathology. Magnetic resonance imaging of his brain demonstrated a well-defined craniopharyngioma with suprasellar extension. His pituitary gland was compressed and the pituitary stalk was displaced by the tumor. He had marked improvement in muscle power and rapid reduction of serum creatine phosphokinase levels paralleling the correction of severe hyponatremia, even before the initiation of hormone replacement., Conclusions: This case illustrates the rare presentation of severe hyponatremia and hyponatremia-induced myopathy in patients with craniopharyngioma, awareness of which would facilitate early appropriate investigations and treatment.

Selective apoptosis of granule cells in the hippocampal dentate gyrus (DG) of rats with bilateral adrenalectomy (ADX) and in patients who died of adrenal insufficiency has been reported. Although adrenal insufficiency is a common disease and is usually associated with hyponatremia, its effect on the central nervous system and in apoptosis in the hippocampus remain to be elucidated. Using rat models to represent clinical hyponatremia accompanying adrenal insufficiency, we show that reduced serum [Na + ] was associated with selective apoptosis in the DG. Nine days after ADX, apoptotic cells were observed in the DG of rats whose serum [Na + ] was <125mEq/L (moderate hyponatremia), but rarely in those whose serum [Na + ] was ≥125mEq/L or in normonatremic rats. Although all hyponatremic ADX rats survived following treatment with corticosterone and saline started 7days after ADX when apoptosis had not yet occurred, selective apoptosis on day 9 was not prevented in moderately hyponatremic rats. Interestingly, treatment with memantine, a noncompetitive NMDAR antagonist, prevented the selective apoptosis in the DG in moderately hyponatremic, ADX rats, and improved electrophysiological dysfunction, including impaired basal synaptic transmission and long-term potentiation at the entorhinal cortex-DG synapses. These results demonstrated that in adrenal insufficient rats, hyponatremia was associated with apoptosis in the DG, and that memantine prevented the apoptosis and improved cell function. Our data imply the importance of assessing the possibility of neurological impairments after treatment with CORT in patients with moderate or severe hyponatremia accompanying adrenal insufficiency and that memantine may represent a beneficial therapeutic strategy to prevent neurological impairments in such patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: To evaluate severe hyponatraemia in foals presenting as medical emergencies to an intensive care unit (ICU) in order to determine the prevalence, clinical findings, primary diagnosis and outcome., Design: Retrospective case study of records from Thoroughbred foals aged less than 3 months presenting to an ICU as medical emergencies in 2002-12; foals with severe hyponatraemia (serum sodium <122 mmol/L) on admission laboratory data were identified. Data retrieved included signalment, clinical findings, laboratory results, primary diagnosis, treatment and outcome., Results: Severe hyponatraemia was identified in 69/1718 Thoroughbred foals (4%) presenting to the ICU during the study period. Of the 69 foals, 11 (15.9%) presented with neurological signs attributable to hyponatraemic encephalopathy and 7 of these foals had seizures; other neurological signs included obtundation, ataxia and apparent blindness. The three most common primary diagnoses of the 69 foals with severe hyponatraemia were renal disease (18/69, 26.1%), enterocolitis (16/69, 23.2%) and uroperitoneum (15/69, 21.7%). Treatment was directed at the primary disease and correction of the hyponatraemia. A total of 50 of the 69 foals (72.5%) with severe hyponatraemia survived to hospital discharge and 38 of them (76%) survived at least 12 months following discharge., Conclusion: The prevalence of severe hyponatraemia in this study population was 4%. The majority of foals with severe hyponatraemia did not demonstrate direct clinical manifestations as a result of the low serum sodium concentration. The outcome of foals with severe hyponatraemia was mostly favourable., (© 2016 Australian Veterinary Association.)

Background: In the context of infectious diseases, mild hyponatremia is supposed to be originated by a transient secretion of vasopressin mediated by non-osmotic stimuli. This study provides data supporting the view that mild hyponatremia during acute illnesses is related to a systemic inflammatory condition., Methods: A total of 328 consecutive children (aged 3 months to 17 years) underwent blood testing at the Pediatric Emergency Department over a 2-month period and were retrospectively analyzed., Results: Hyponatremia was found in 98 patients, and in most of them it was a mild condition. A significant trend towards lower levels of plasmatic sodium, along with the increase of C-reactive protein, was observed., Conclusions: A significant relationship between plasmatic sodium levels and C-reactive protein was found, apart from of the underlying disease.

Objective: European guidelines do not recommend tolvaptan for treatment of syndrome of inappropriate antidiuretic hormone secretion (SIADH), principally owing to concerns about risk of overly rapid correction of hyponatraemia. This study evaluated the real-life effectiveness and safety of tolvaptan., Design: Consecutive case series., Patients: Inpatients treated with tolvaptan for SIADH in 2 UK hospitals over a 3-year period., Measurements: The primary outcome measures were serum sodium (sNa) correction at 24 and 48 h after tolvaptan therapy., Results: This case series included 61 patients aged 74·4 ± 15·3 years with (mean ± SD) sNa 119·9 ± 5·5 mmol/l. The mean sNa increase 24 h after tolvaptan initiation was 9 ± 3·9 mmol/l. Excessive correction of hyponatraemia was observed in 23% of patients with all these patients having baseline sNa <125 mmol/l, but no cases of osmotic demyelination syndrome were recorded. At the end of tolvaptan therapy, sNa increase was 13·5 ± 5·9 mmol/l with 96·7% of patients having sNa increase ≥5 mmol/l in 48 h. There was a negative significant correlation (P = 0·012) between baseline sNa and 24-h change; for every 1 mmol/l reduction in baseline value, sNa increased by an additional 0·23 mmol/l (95% CI 0·05-0·41)., Conclusions: Tolvaptan is effective in correcting hyponatraemia. Without rigorous electrolyte monitoring, tolvaptan carries a significant risk of overly rapid sodium correction, especially in patients with starting sNa <125 mmol/l. Tolvaptan should be used with great caution under close electrolyte monitoring., (© 2015 John Wiley & Sons Ltd.)

Copeptin is part of the 164 amino acid precursor protein preprovasopressin together with vasopressin and neurophysin II. During precursor processing, copeptin is released together with vasopressin. Copeptin concentrations respond as rapidly as vasopressin to changes in osmolality, a decrease in blood pressure or stress and there is a close correlation of vasopressin and copeptin concentrations. For these reasons, copeptin is propagated as a surrogate marker for vasopressin in the differential diagnosis of the polyuria-polydipsia syndromes and hyponatremia. Results of prospective studies show that a baseline copeptin level without prior fluid deprivation >20 pmol/L is able to identify patients with nephrogenic diabetes insipidus, whereas osmotically stimulated copeptin levels differentiate between patients with partial central diabetes insipidus and primary polydipsia with a high sensitivity and specificity >94%. In hyponatremia, low copeptin levels point to primary polydipsia and high levels to hypovolemic hyponatremia. The copeptin to urinary sodium ratio differentiates accurately between volume-depleted and normovolemic disorders., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Purpose: To evaluate the effect of chronic mild hyponatremia ([Na+]=130-137mmol/L) on bone mineral content (BMC) and bone mineral density (BMD) loss through multiple, serial dual-energy X-ray absorptiometry (DXA) scans., Methods: Utilizing biochemical and DXA scan data from two Danish regions between 2004 and 2011, supplemented with national Danish patient diagnosis and prescription reimbursement databases, a retrospective cohort study was performed. All subjects with more than one DXA scan were included, then stratified into "normonatremia" ([Na(+)]=[137.00-147.00] mmol/L) and "mild hyponatremia" ([Na(+)]=[130.00-137.00[mmol/L) based on mean and confidence interval (CI) values calculated from all plasma sodium measurements between each subject's first and last DXA scan. Baseline, follow-up and delta values for hip and lumbar spine BMC and BMD were estimated between groups, then adjusted for comorbidity and medication use., Results: Hip and lumbar spine groups had 884 and 1069 patients with "normonatremia" versus 58 and 58 patients with "mild hyponatremia", respectively. Mild hyponatremia was associated with lower BMC and BMD in nearly all regions of the hip, and with worse losses in the trochanteric, femoral neck and total hip regions. Mild hyponatremia had limited effect on the lumbar spine., Conclusions: Chronic mild hyponatremia seems to greatly affect bone in the hip, while the effect is limited in the lumbar spine. We suggest further retrospective study of patients with moderate (P-Na=120-130mmol/L) to severe hyponatremia (P-Na<120mmol/L) and prospective studies to further examine the association., (Copyright © 2015 Elsevier Inc. All rights reserved.)

We herein describe a second Japanese case of sarcoidosis presenting Addison's disease. A 52-year-old man was diagnosed with sarcoidosis based on clinical and laboratory findings, including bilateral hilar lymphadenopathy and elevated levels of serum angiotensin-converting enzyme and lysozyme, as well as the presence of noncaseating epithelioid granulomas. The patient also exhibited general fatigue, pigmentation, weight loss, hypotension and hyponatremia, suggestive of chronic adrenocortical insufficiency. An endocrine examination confirmed primary adrenocortical insufficiency. This case suggests the direct involvement of sarcoid granuloma in the adrenal glands.

Porphyria is a group of eight metabolic disorders characterized by defects in heme biosynthesis. The presentation of porphyria is highly variable, and the symptoms are nonspecific, which accounts in part for delays in establishing a diagnosis. In this study, we report the characteristics of 36 Chinese acute porphyria patients. Most of them were female (33/36), and the median age was 25.3 years (range 18-45 years). The most frequent presenting symptom was abdominal pain (32/36). Hyponatremia was the most common electrolyte abnormality (29/36), and the serum sodium concentration was significantly negatively correlated with convulsion ( p = 0.00). Genetic testing provided a precise diagnosis of the patients. Genetic analysis of the porphobilinogen deaminase ( PBGD ) gene was performed for 10 subjects. Of them, 9 were found to harbor a mutation in the PBGD gene, proving a diagnosis of acute intermittent porphyria, and, in 1 case, a novel Cys209Term mutation was found., Competing Interests: The authors declare that there is no conflict of interests regarding the publication of this paper.

Disturbance of calcium homeostasis is implicated in the normal process of aging and brain pathology prevalent in the elderly such as Alzheimer's, Parkinson's, and amyotrophic lateral sclerosis. Previous studies demonstrated that applying a hyponatremic iso-osmotic (low-NaCl) artificial cerebrospinal fluid (ACSF) to rodent hippocampus causes extracellular calcium to rapidly decrease. Restoring normonatremia after low-NaCl treatment causes a rapid increase in extracellular calcium that overshoots baseline. This study examined the amplitude, timing, and mechanism of these surprising calcium changes. We also tested whether hyponatremia increased calcium entry into brain cells or calcium binding to chondroitin sulfate (CS), a negatively charged constituent of the extracellular matrix (ECM) that may be occupied by sodium during normonatremia. We report three major findings. First we show that CS does not contribute to extracellular calcium changes during low-NaCl treatments. Second, we show that the time to minimum extracellular calcium during low-NaCl treatment is significantly shorter than the time to maximum extracellular calcium in recovery from low-NaCl treatment. Third, we show that the decrease in extracellular calcium observed during hyponatremia is attenuated by ML 218, a highly selective T-type calcium channel blocker. Together these data suggest that calcium rapidly enters cells at the onset of low-NaCl treatment and is extruded from cells when normonatremia is restored. Calcium binding to CS does not significantly contribute to calcium changes in brain during hyponatremia. Differences in timing suggest that extracellular calcium changes during and in recovery from hyponatremia occur by distinct mechanisms or by a multistep process. Finally, partial block of extracellular calcium influx by ML 218 suggests that T-type channels are involved in calcium entering cells during hyponatremia. Given the high prevalence of hyponatremia among elderly patients and the growing understanding of calcium's role in multiple neurologic pathologies, this study promotes a novel approach for studying and potentially preventing the effects of hyponatremia on calcium dysregulation in brain tissue., (Copyright © 2015. Published by Elsevier Inc.)

We present 3 cases of severe hyponatremia occurring on a commercially guided river rafting trip on the Colorado River in Grand Canyon National Park. All 3 women appeared to have been overhydrating because of concern about dehydration and required evacuation within 24 hours of each other after the staggered onset of symptoms, which included fatigue and emesis progressing to disorientation or seizure. Each was initially transferred to the nearest hospital and ultimately required intensive care. Imaging and laboratory data indicated all 3 patients had hypervolemic hyponatremia. Unlike the well-documented exercise-associated hyponatremia cases commonly occurring in prolonged endurance athletic events, these 3 unique cases of acute hyponatremia were not associated with significant exercise. The cases illustrate the diagnostic and treatment challenges related to acute hyponatremia in an austere setting, and underscore the importance of preventive measures focused on avoidance of overhydration out of concern for dehydration., (Published by Elsevier Inc.)

We present a case of rapidly progressing Addison's disease in adrenal crisis with severe hyponatraemia and absence of hyperkalaemia in a 10-year-old girl. She presented with 2 weeks of vomiting, fatigue and weight loss. Her serum electrolytes obtained 1 week prior to presentation were normal, except for mild hyponatraemia at 131 mmol/L, which dropped to 112 mmol/L on admission. She had normal serum potassium, low-serum osmolality, with elevated urine sodium and osmolality, indistinguishable from syndrome of inappropriate antidiuretic hormone (SIADH). Subsequently, Addison's disease was diagnosed on the basis of gingival hyperpigmentation and undetectable cortisol on adrenocorticotropic hormone stimulation test. She rapidly responded to stress dose hydrocortisone, followed by hydrocortisone and fludrocortisone replacement therapy. The absence of hyperkalaemia in the presence of severe hyponatraemia cannot rule out Addison's disease in children. The mechanism of hypo-osmolar hyponatraemia in primary adrenal insufficiency and clinical clues to differentiate it from SIADH are discussed., (2015 BMJ Publishing Group Ltd.)

Pseudohyponatremia has been reported in association with severe hypertriglyceridemia and hyperparaproteinemia, but its association with severe hypercholesterolemia is not well-known. We report a 43-year-old woman with refractory primary biliary cirrhosis who presented with asymptomatic hyponatremia (121 mmol/L; normal range: 135-145 mmol/L). She was ultimately found to have a total serum cholesterol level of 2415 mg/dL (normal range: 120-199 mg/dL) - secondary to accumulation of lipoprotein-X-causing pseudohyponatremia. The diagnosis was confirmed by measurement of serum osmolality (296 mOsm/kg H2O; normal range: 270-300 mOsm/kg H2O) and serum sodium by direct potentiometry (141 mmol/L). Furthermore, following 16 sessions of plasmapheresis over a 4-month period, there was marked lowering of serum cholesterol to 200 mg/dL and normalization of serum sodium (139 mmol/L) as measured by indirect potentiometry. This case shows that extreme hypercholesterolemia from elevation of lipoprotein-X particles in cholestasis can be a rare cause of pseudohyponatremia. It highlights the need to measure serum sodium with direct potentiometry in the setting of extreme hypercholesterolemia and consider this possibility before initiating treatment of hyponatremia., (Published by Elsevier Inc.)

Unlabelled: Craniopharyngioma is associated with a wide and interesting variety of sodium states both by itself and following surgical resection. These are often challenging to diagnose, especially given their dynamic nature during the perioperative course. We present the case of a boy with craniopharyngioma who had hyponatremia due to cerebral salt wasting preoperatively, developed diabetes insipidus (DI) intraoperatively and proceeded to develop hypernatremia with adipsic DI., Conclusion: Cerebral salt wasting is a rare presenting feature of craniopharyngioma. Postoperative DI can be associated with thirst abnormalities including adipsia due to hypothalamic damage; careful monitoring and a high index of suspicion are required for its detection. Adipsic DI is a difficult condition to manage; hence a conservative surgical approach is suggested.

Background: Extra-pulmonary small cell carcinoma (EPSCC) is a rare cause of malignancy, representing 2.5-5 % of all small cell carcinomas, with an incidence rate of 1000 cases per year in the USA. The purpose of this study is to characterize the location, extent of disease, and survival of patients with EPSCC, and to analyze potential clinical prognostic indicators predicting survival., Methods: A retrospective review of all patients with EPSCC between the years 2000 and 2010 was conducted. Patients included for analysis had pathologic diagnosis of EPSCC, poorly differentiated tumors, and negative chest imaging at diagnosis., Results: 53 patients were included in the analysis. 23 patients (43 %) had limited disease (LD) at diagnosis, and 30 patients (57 %) had extensive disease (ED) at diagnosis. Carcinoma of unknown primary represented the largest proportion of patients (40 %), followed by genitourinary (26 %), gastrointestinal (15 %), head and neck (11 %), gynecologic (6 %), and breast (2 %). The median overall survival (OS) was 4.7 months; 14.5 months for LD, and 3.7 months for ED. Genitourinary EPSCC had the best median OS at 13.1 months, and GI carcinomas had the worst at 1.7 months. On univariate analysis, ED (p = 0.0001), non-genitourinary EPSCC (p = 0.036), and hyponatremia were associated with worse OS (p = 0.0176)., Conclusions: In a cohort of patients with EPSCC, hyponatremia, non-genitourinary EPSCC, and extensive disease were associated with worse OS. Anatomic site predicted survival, which suggests that pathologic heterogeneity between individual tumor sites, including mixed tumor pathology, may affect the prognosis of this rare disease. Future directions for research should include thorough pathologic and genetic profiles.

Background: Many diagnostic procedures are conducted in patients with syndrome of inappropriate antidiuresis (SIAD). However, the contribution in identification of the cause of SIAD remains unknown., Methods: The study was conducted at Kaohsiung Veterans General Hospital in southern Taiwan. From January 2000 to December 2009, medical records of 439 adult patients hospitalized for new-onset SIAD at a single center were retrospectively collected. All diagnostic procedures during hospitalization were divided into four groups: chest/lung, central nervous system, abdomen, and bone marrow to evaluate their positive rate leading to the cause of SIAD. Factors associated with "procedures leading to the cause" were also analyzed to improve efficacy of survey., Results: Cause of SIAD was identified in 267 (60.8%). Of them, 150 were pulmonary disorders, 44 were drugs, 37 were central nervous system disorders, 32 were malignancy and 4 were post-surgery. Survey for chest/lung, central nervous system, abdomen, and bone marrow were performed in 96.6%, 29.2%, 38.0% and 3.6% of patients, respectively; positive findings leading to the cause of SIAD were 39.6%, 12.5%, 5.3% and 6.3%, respectively. Among the diagnostic procedures, chest x-ray (424/439, 96.6%) was most frequently performed with the highest identification rate of 34.7% (147 cases). Major significant independent factors that associated with "procedure leading to a cause" were: absence of SIAD-associated drug history, presence of fever/chills, and presence of respiratory symptoms. Cause of SIAD became evident later during the follow-up period in 10 of 172 (5.8%) patients who were initially thought to be cause-unknown. Malignancy was the cause for 5 cases and pulmonary tuberculosis was for the other five. Eight of these causes became evident within one year after the diagnosis of SIAD., Conclusions: SIAD with unidentified causes were prevalent. Current diagnostic procedures remain not satisfying in determining the cause of SIAD, but chest radiograph did demonstrate higher diagnostic rate, especially in patients presented with fever, chills, respiratory symptoms, and without SIAD-associated drug history. Patients with unidentified cause should be followed for at least one year when most hidden causes (e.g. malignancy and tuberculosis) become obvious.