Severe hyponatremia and diabetes insipidus caused by low-dose cyclophosphamide in breast cancer patients: A case report and literature review.

RATIONALE: Cyclophosphamide (CTX) is widely used in the treatment of malignancies and autoimmune diseases. Although severe hyponatremia caused by low-dose CTX chemotherapy is uncommon, it can lead to serious complications and even death. PATIENT CONCERNS: A 44-year-old woman with left-sided breast cancer suddenly experienced headaches, disorientation and weakness after receiving low-dose neoadjuvant chemotherapy combined with CTX and doxorubicin. DIAGNOSES: The patient pathology showed invasive breast carcinoma. She developed severe hyponatremia and a generalized seizure after completing the first cycle of neoadjuvant chemotherapy with CTX and doxorubicin. Laboratory tests showed a serum sodium of 118 mmol/L (normal range 135-145 mmol/L) and potassium sodium 3.16 mmol/L (normal range 3.5-5.5 mmol/L). Subsequently, the patient developed secondary diabetes insipidus 4 hours after sodium supplementation, her 24-hour urine volume was 4730 mL (normal range 1000-2000 mL/24 hours), and the urine specific gravity decreased to 1.005. INTERVENTIONS: The patient was given intravenous sodium chloride (500 mL of 3%NaCl, 100 mL/hour) and potassium chloride (500 mL of 0.3%KCl, 250 mL/hour). Meanwhile, she was advised to reduce her water intake, and pituitrin was administered to prevent dehydration caused by diabetes insipidus. OUTCOMES: The patient completely recovered after correcting of the serum sodium concentration (137 mmol/L) without any neurological deficits. After discontinuing pituitrin, her 24-hour urine volume was 2060 mL and the urine specific gravity was 1.015. LESSONS: This is a typical case of severe hyponatremia induced by low-dose CTX. Clinicians and healthcare providers should be aware of this potential toxicity, and appropriate monitoring should be implemented.

Pearls & Oy-sters: Syndrome of Inappropriate Antidiuretic Hormone Secretion Presenting as Neuromyelitis Optica Spectrum Disorder Flare.

While it was previously believed that neuromyelitis optic spectrum disorder (NMOSD) mostly affected the optic nerves and the spinal cord, it is increasingly recognized that NMOSD can involve any area of the CNS where aquaporin-4 is highly expressed. These other areas can include the hypothalamus and the circumventricular organs that surround the third and fourth ventricles, serving as osmoregulators. The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is one of the most common causes of hyponatremia and has been associated with NMOSD due to these lesions. In this report, we present a case of a patient with known NMOSD, who presented with dizziness, fatigue, and generalized weakness and whose workup revealed hyponatremia in the setting of SIADH and hypothalamic demyelinating lesions. This case illustrates an atypical presentation of NMOSD and the importance of looking for syndromes, such as SIADH. This can guide diagnostic testing, such as getting thin MRI cuts through the hypothalamus and brainstem, as well as advanced management techniques such as immunotherapy.

Hyperbilirubinemia and Hyponatremia as Predictors of Complicated Appendicitis.

Several studies have reported elevated serum bilirubin or reduced serum sodium levels in patients with complicated appendicitis (CA). This study examined the efficacy of hyperbilirubinemia, hyponatremia, and both combined in the preoperative diagnosis of CA. Patients who underwent surgery for acute appendicitis were included in this retrospective review. In total, 247 patients were included in the final analysis. Of these, 36 (14.2%) had early appendicitis, 177 (72.0%) had acute suppurative appendicitis, 32 (13.0%) had necrotizing/gangrenous acute appendicitis, and 2 (0.8%) had other types of appendicitis. The mean total bilirubin (TBIL) level was significantly higher in patients with CA than in those with uncomplicated appendicitis. Conversely, the mean serum sodium level was significantly lower in patients with CA than in those with uncomplicated appendicitis. The levels of TBIL (odds ratio: 1.098, 95% CI: 1.052-1.147) and serum sodium (odds ratio: 0.743, 95% CI: 0.646-0.855) were associated with CA. Hyponatremia combined with hyperbilirubinemia yielded significant discriminatory value for the diagnosis of CA. TBIL and serum sodium levels can be considered as adjuvant parameters in the diagnosis of perforated/necrotizing appendicitis. Although hyperbilirubinemia and hyponatremia together were better able to determine the risk of CA than either marker alone, other markers are required to definitively predict CA. Furthermore, large-scale studies are needed to confirm these findings.

The osmotic demyelination syndrome: the resilience of thalamic neurons is verified with transmission electron microscopy.

The development of a murine model of osmotic demyelinating syndrome (ODS) allowed to study changes incurred in extrapontine zones of the CNS and featured neuron and glial cell changes in the relay thalamic ventral posterolateral (VPL) and ventral posteromedial (VPM) nuclei before, during and after ODS induction, and characterized without immune response. There, the neuron Wallerian-type deteriorations were verified with fine structure modifications of the neuron cell body, including some nucleus topology and its nucleolus changes. Morphologic analyses showed a transient stoppage of transcriptional activities while myelinated axons in the surrounding neuropil incurred diverse damages, previously reported. Even though the regional thalamus myelin deterioration was clearly recognized with light microscopy 248 h after osmotic recovery of ODS, ultrastructure analyses demonstrated that, at that time, the same damaged parenchyma regions contained nerve cell bodies that have already reactivated nucleus transcriptions and neuroplasm translations because peculiar accumulations of fibro-granular materials, similar to those detected in restored ODS astrocytes, were revealed in these restructuring nerve cell bodies. Their aspects suggested to be accumulations of ribonucleoproteins. The findings suggested that progressive neural function's recovery in the murine model could imitate some aspects of human ODS recovery cases.

Ultrastructural Analysis of Thalamus Damages in a Mouse Model of Osmotic-Induced Demyelination.

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.

Chronic hyponatremia and association with osteoporosis among a large racially/ethnically diverse population.

Chronic hyponatremia may contribute to decreased bone density. We studied 341,003 men and women who underwent DXA testing and observed that individuals with chronic hyponatremia (sodium < 135 mEq/L) had an 11% greater likelihood of having osteoporosis. There was a dose-dependent effect with lower sodium and stronger association with osteoporosis. INTRODUCTION: Chronic hyponatremia has been associated with both neurologic deficits and increased risk of gait abnormalities leading to falls and resultant bone fractures. Whether chronic hyponatremia contributes to decreased bone density is uncertain. We evaluated whether chronic, mild hyponatremia based on serial sodium measurements was associated with increased risk of osteoporosis within a large, ethnically diverse population. METHODS: This is a retrospective cohort study between January 1, 1998 and December 31, 2014 within Kaiser Permanente Southern California, an integrated healthcare delivery system. Men and women were aged ≥ 55 years with ≥ 2 serum sodium measurements prior to dual-energy X-ray absorptiometry (DXA) testing. Time-weighted (TW) mean sodium values were calculated by using the proportion of time (weight) elapsed between sodium measurements and defined as < 135 mEq/L. Osteoporosis defined as any T-score value ≤ - 2.5 of lumbar spine, femoral neck, or hip. RESULTS: Among 341,003 individuals with 3,330,903 sodium measurements, 11,539 (3.4%) had chronic hyponatremia and 151,505 (44.4%) had osteoporosis. Chronic hyponatremic individuals had an osteoporosis RR (95% CI) of 1.11 (1.09, 1.13) compared to those with normonatremia. A TW mean sodium increase of 3 mEq/L was associated with a lower risk of osteoporosis [adjusted RR (95% CI) 0.95 (0.93, 0.96)]. A similar association was observed when the arithmetic mean sodium value was used for comparison. CONCLUSIONS: We observed a modest increase in risk for osteoporosis in people with chronic hyponatremia. There was also a graded association between higher TW mean sodium values and lower risk of osteoporosis. Our findings underscore the premise that chronic hyponatremia may lead to adverse physiological effects and responses which deserves better understanding.

Hyponatremia, bone mineral density and falls in the elderly; Results from AHAP study.

BACKGROUND: Hyponatremia (HN) can be associated with osteoporosis, falls and bone fractures in the elderly. Recent researches demonstrated different results about the correlation of HN with bone mineral density and bone fractures. METHODS: This analytic research came from the AHAP project in northern IRAN. All people aged 60 years and over were included in the study. Individuals with severe comorbidities and then who had concurrent conditions which could have impact on bone mineral densities (BMD) such as long-term use of steroids, calcium and/or vitamin D supplements, bisphosphonates, calcitonin, thiazides and hormonal medications were excluded. RESULTS: One thousand and one hundred and thirteen older persons entered in the study. More than 10 percent of the participants had HN (serum Na+ level ≤ 137mEq/L). No significant difference has been observed between hyponatremic and nonhyponatremic individuals about their balance abilities; bone mineral density; incidence of falls and/or bone fracture during the previous 6 months; dependency in activities of daily living; and osteoporosis. CONCLUSION: HN was not a prevalent problem in older adults who met the inclusion criteria of this research. No significant difference has been observed between HN and bone mineral density and falls in the elderly.

Effect of single-dose of tolvaptan in neurocritical patients with hyponatremia due to syndrome of inappropriate antidiuretic hormone secretion / Efecto de una dosis única de tolvaptán en pacientes neurocríticos con hiponatremia debido a SIADH

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Hyponatremia in an Elderly Patient due to Isolated Hypoaldosteronism Occurring after Licorice Withdrawal.

Hyponatremia is one of the most common electrolyte disorders encountered in the elderly. We present the case of an 81-year-old man who developed hyponatremia due to isolated hypoaldosteronism occurring after licorice withdrawal. He had severe hypokalemia with hypertension and was diagnosed with pseudoaldosteronism. He had been taking a very small dose of licorice as a mouth refresher since his early adulthood. Five months after licorice withdrawal, he developed hypovolemic hyponatremia, which was resolved with administration of fludrocortisone acetate. Our experience with this case suggests that isolated hypoaldosteronism occurring after licorice withdrawal should be considered as a potential cause of hyponatremia in elderly patients.

Hyponatremia as a powerful prognostic predictor for Japanese patients with clear cell renal cell carcinoma treated with a tyrosine kinase inhibitor.

BACKGROUND: We aimed to evaluate the prognostic significance of hyponatremia in patients with metastatic clear cell renal cell carcinoma (RCC) treated with a tyrosine kinase inhibitor (TKI). METHODS: This study included a total of 209 consecutive Japanese patients undergoing radical nephrectomy who were subsequently treated with either sunitinib or sorafenib as a first-line therapy for metastatic clear cell RCC. In this series, normal natremia and hyponatremia prior to the introduction of TKI was defined as a serum sodium level >136 and ≤136 mEq/L, respectively. RESULTS: Patients were classified into 165 (78.9 %) with normal natremia and 44 (21.1 %) with hyponatremia. Progression-free survival (PFS) in the hyponatremia group (median 10.0 months) was significantly poorer than that in the normal natremia group (median 28.4 months). Overall survival (OS) in the hyponatremia group (median 20.9 months) was significantly poorer than that in the normal natremia group (median 38.5 months). Multivariate analyses identified hyponatremia, in addition to the existence of sarcomatoid components in radical nephrectomy specimens, high serum C-reactive protein levels, and low serum albumin levels, as poor prognostic factors for both PFS and OS. There were significant differences in both PFS and OS according to the number of these 4 independent risk factors that were positive (negative for any risk factors vs positive for 1 or 2 risk factors vs positive for 3 or 4 risk factors). CONCLUSIONS: Hyponatremia appears to be one of the most powerful prognostic predictors in Japanese patients treated with a TKI as a first-line agent against metastatic clear cell RCC.

The incidence of postoperative hyponatremia and associated neurological sequelae in children with intracranial neoplasms.

OBJECT: Intracranial tumors are common pediatric neoplasms and account for substantial morbidity among children with cancer. Hyponatremia is a known complication of neurosurgical procedures and is associated with higher morbidity among neurosurgical patients. The authors aimed to estimate the incidence of hyponatremia, identify clinical characteristics associated with hyponatremia, and assess the association between hyponatremia and patient outcome among children undergoing surgery for intracranial tumors. METHODS: This is a retrospective cohort study of children ranging in age from 0 to 19 years who underwent an initial neurosurgical procedure for an intracranial tumor between January 2001 and February 2012. Hyponatremia was defined as serum sodium ≤ 130 mEq/L during admission. RESULTS: Hyponatremia during admission occurred in 39 (12%) of 319 patients and was associated with young age and obstructive hydrocephalus (relative risk [RR] 2.9 [95% CI 1.3-6.3]). Hyponatremic patients were frequently symptomatic; 21% had seizures and 41% had altered mental status. Hyponatremia was associated with complicated care including mechanical ventilation (RR 4.4 [95% CI 2.5-7.9]), physical therapy (RR 4 [95% CI 1.8-8.8]), supplemental nutrition (RR 5.7 [95% CI 3.3-9.8]), and infection (RR 5.7 [95% CI 3.3-9.5]). Hyponatremic patients had a 5-fold increased risk of moderate or severe disability on the basis of their Pediatric Cerebral Performance Category score at discharge (RR 5.3 [95% CI 2.9-9.8]). Obstructive hydrocephalus (adjusted odds ratio [aOR] 3.24 [95% CI 1.38-8.94]) and young age (aOR 0.92 [95% CI 0.85-0.99]) were independently associated with hyponatremia during admission. Hyponatremia was independently associated with moderate or worse disability by Pediatric Cerebral Performance Category score at discharge (aOR 6.2 [95% CI 3.0-13.03]). CONCLUSIONS: Hyponatremia was common, particularly among younger children and those with hydrocephalus. Hyponatremia was frequently symptomatic and was associated with more complicated hospital courses. Hyponatremia was independently associated with worse neurological outcome when adjusted for age and tumor factors. This study serves as an exploratory analysis identifying important risk factors for hyponatremia and associated sequelae. Further research into the causes of hyponatremia and the association with poor outcome is needed to determine if prevention and treatment of hyponatremia can improve outcomes in these children.

Acrodermatitis enteropática en paciente con ileostomía de alto débito / Enteropathic acrodermatitis in a patient with high-out-put ileostomy

La deficiencia de zinc es relativamente frecuente en ciertas patologías, pero su manifestación clínica es rara. Se expone el caso de un paciente que ingresó con cuadro de deshidratación hiponatrémica e insuficiencia prerrenal secundaria por ileostomía de alto débito e intolerancia oral. Aunque se normalizó el débito de la ilesotomía al tercer día del ingreso y los niveles plasmáticos de zinc iniciales fueron normales, el paciente después de estar con NPT suplementada con 13 mg/día de zinc, sufrió una deficiencia severa de zinc con acrodermatitis enteropática que se resolvió completamente después de una semana con 26,5mg/día. Sin embargo, los niveles plasmáticos no se normalizaron hasta pasado un mes de estar en tratamiento con estas macrodosis de zinc. El zinc plasmático no es un buen indicador de los depósitos de zinc en el organismo, y muchas veces, su alteración es un indicador tardío de deficiencia. Tampoco se observa una correlación entre la mejoría clínica y la normalización de sus niveles, siendo frecuente la resolución clínica a los pocos días de la suplementación sin detectarse aumento de zinc en plasma (AU)

Zinc deficiency is relatively common in certain pathologies, although its clinical manifestation is uncommon. We present the case of a patient who was admitted pre -senting hyponatremic dehydration and pre-renal failure secondary to high-output ileostomy and oral intolerance. Although the ileostomy output was normalized within 3days of admission and initial zinc plasma levels were normal, after being fed with TPN supplemented with 13mg/day of zinc, he suffered a severe zinc deficit with enteropathicacrodermatitis that was completely resolved after one week with 26.5 mg/day. However, plasma levels did not return to normal until one month on therapy with high doses of zinc. Zinc plasma levels are not a good indicator of zinc stores in the body and many times their changes are a late indicator of zinc deficit. There is not a correlation between the clinical improvement and normalization of zinc levels, being common the clinical resolution within few days of the supplementation without observing an increase of zinc plasma levels (AU)

Impact of hyponatremia on survival of patients with metastatic renal cell carcinoma treated with molecular targeted therapy.

OBJECTIVES: Hyponatremia is reported to be associated with poor survival in localized renal cell carcinoma and metastatic renal cell carcinoma treated with immunotherapy. However, there are no reports on the relationship between hyponatremia and prognosis of metastatic renal cell carcinoma treated with molecular targeted therapy. We evaluated the prognostic significance of hyponatremia in metastatic renal cell carcinoma treated with molecular targeted therapy as first-line therapy. METHODS: We retrospectively analyzed a database comprising 87 patients treated from April 2008 to July 2011 with sorafenib or sunitinib as first-line therapy for metastatic renal cell carcinoma. Patients were divided into three groups according to serum sodium level: severe hyponatremia (≤134 mEq/L), mild hyponatremia (135-137 mEq/L) and normal natremia (≥138 mEq/L). RESULTS: Median cancer-specific survival time was 8.8 months in the patients with severe and mild hyponatremia, and 32.6 months in the patients with normal natremia (P < 0.001). Multivariate analysis showed severe and mild hyponatremia to be significantly associated with cancer-specific survival (hazard ratio 6.228; 95% confidence interval 2.161-17.947, P = 0.001; hazard ratio 3.374; 95% confidence interval 1.294-8.798, P = 0.013), respectively. Neutrophilia and high C-reactive protein level (C-reactive protein ≥1.0 mg/dL) were significant prognostic factors to predict inferior cancer-specific survival. In Harrell's concordance index calculation, hyponatremia could significantly improve the predictive accuracy for estimation of survival probability (P = 0.028). CONCLUSIONS: Hyponatremia (<138 mEq/L), neutrophilia and high C-reactive protein levels seem to represent significant predictive factors for cancer-specific survival in metastatic renal cell carcinoma patients treated with molecular targeted therapy as first line therapy. Furthermore, hyponatremia might be significantly associated with chronic inflammation and tumor aggressiveness.

Impending cardiac tamponade caused by salt supplement in a hyponatremic patient with chronic kidney disease.

We documented a hyponatremic patient who developed imminent cardiac tamponade upon oral salt supplement. A 72-year-old diabetic woman had hemorrhagic stroke; pericardial effusion; and chronic kidney disease, stage IV. She developed hyponatremia (serum sodium level, 125 mmol/L), compatible with the syndrome of inappropriate antidiuretic hormone, and received oral salt supplement 9 g/d for 4 days. Shortness of breathing and increasing heart rate ensued, and the echocardiography found accumulation of pericardial effusion with signs of impending cardiac tamponade. Pig-tail drainage through pericardiocentesis was done, and the vital signs were stabilized. We found the production of pericardial effusion increased from 100 to 220 mL/d after oral salt supplement at 3 g/d was reassumed. We discuss the relationship between serum sodium levels, the dose of salt supplement and the accumulation of pericardial effusion.

Cyclophosphamide-induced symptomatic hyponatraemia.

Cyclophosphamide is an alkylating agent used in antineoplastic and immunosuppressive therapies. Symptomatic hyponatraemia is a rare but life-threatening complication in patients treated with cyclophosphamide. We report the case of a 64-year-old woman with breast cancer who developed severe symptomatic hyponatraemia with a generalised seizure and convulsions after a second cycle of adjuvant chemotherapy with 5-fluouracil, epirubicin and cyclophosphamide. She completely recovered after correction of the serum sodium concentration without neurological deficits. Physicians prescribing cyclophosphamide, irrespective of the treatment indication and dosage, should be aware of this potentially life-threatening complication.