Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis

Restuccia, Tea; Gómez‐Anson, Beatriz; Guevara, Mónica; Alessandria, Carlo; Torre, Aldo; Alayrach, M. Elena; Terra, Carlos; Martín, Miguel Martínez; Castellvı́, Magda; Rami, Lorena; Sáinz, Á.Guttiérez; Ginès, Pere; Arroyo, Vicente

doi:10.1002/hep.20237

Cited by 97 publications

(60 citation statements)

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“…In fact, it has been demonstrated that low serum sodium levels in patients with cirrhosis are associated with a remarkable reduction in the cerebral concentration of organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine, as a consequence of hyperammonemia, and low extracellular sodium. [21][22][23] In experimental models of acute liver failure, the presence of hyponatremia is associated with larger brain swelling compared with normal serum sodium concentration. 24 Finally, in patients with acute liver failure and grade IV hepatic encephalopathy, the administration of hypertonic saline to increase serum sodium concentration reduces the incidence and severity of intracranial hypertension compared with a control group of patients receiving the standard of care.…”

Section: Discussionmentioning

confidence: 99%

Hyponatremia in cirrhosis: Results of a patient population survey

et al. 2006

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and the CAPPS InvestigatorsLow serum sodium concentration is an independent predictor of mortality in patients with cirrhosis, but its prevalence and clinical significance is unclear. To evaluate prospectively the prevalence of low serum sodium concentration and the association between serum sodium levels and severity of ascites and complications of cirrhosis, prospective data were collected on 997 consecutive patients from 28 centers in Europe, North and South America, and Asia for a period of 28 days. The prevalence of low serum sodium concentration as defined by a serum sodium concentration <135 mmol/L, <130 mmol/L, <125 mmol/L, and <120 mmol/L was 49.4%, 21.6%, 5.7%, and 1.2%, respectively. The prevalence of low serum sodium levels (<135 mmol/L) was high in both inpatients and outpatients (57% and 40%, respectively). The existence of serum sodium <135 mmol/L was associated with severe ascites, as indicated by high prevalence of refractory ascites, large fluid accumulation rate, frequent use of large-volume paracentesis, and impaired renal function, compared with normal serum sodium levels. Moreover, low serum sodium levels were also associated with greater frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome, but not gastrointestinal bleeding. Patients with serum sodium <130 mmol/L had the greatest frequency of these complications, but the frequency was also increased in patients with mild reduction in serum sodium levels (131-135 mmol/L). In conclusion, low serum sodium levels in cirrhosis are associated with severe ascites and high frequency of hepatic encephalopathy, spontaneous bacterial peritonitis, and hepatorenal syndrome. (HEPATOLOGY 2006;44:1535-1542 I mpairment in body water homeostasis is a common feature of advanced cirrhosis. [1][2][3] This is characterized by a higher rate of renal retention of water in relation to sodium due to a reduction in solute-free water clearance. The consequent inability to adjust the amount of water excreted in the urine to the amount of water ingested leads to dilutional hyponatremia. In recent years, great advances have been made in the knowledge of the pathogenesis of reduced solute-free water clearance in patients with advanced cirrhosis. The inability to excrete an adequate amount of solute-free water in the urine is related to several factors, the most important of which is increased vasopressin release. A reduction of effective circulating volume due to arterial splanchnic vasodilation is considered the afferent factor leading to a baroreceptormediated nonosmotic stimulation of vasopressin release in cirrhosis. 4 Additional factors in the pathogenesis of hyponatremia in cirrhosis are thought to be reduced production of solute-free water due to a reduced sodium delivery to the distal tubule as a consequence of reduction of glomerular filtration rate and/or increase of sodium reabsorption in the proximal tubule. [4][5][6][7] Several studies in large cohorts of patients with cirrhosis have shown that the renal ability to...

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Section: Discussionmentioning

confidence: 99%

Hyponatremia in cirrhosis: Results of a patient population survey

et al. 2006

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“…15,16 Both hyperammonemia and hyponatremia have the ability to produce swelling of susceptible cells by altering the osmotic balance. [17][18][19] It is known that p38 mitogen-activated protein kinase (p38 MAPK ) acts as an osmosensor which is activated in response to increased cell hydration or swelling. 20,21 Therefore, we chose to explore the effect of ammonia on neutrophil functions such as phagocytosis and oxidative burst and whether activation of the p38 MAPK plays a role in this process by studying normal neutrophils in vitro incubated with different concentrations of ammonia and under hyponatremic conditions, as well as in a hyperammonemic rat model.…”

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confidence: 99%

Ammonia impairs neutrophil phagocytic function in liver disease†

et al. 2008

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Hyperammonemia is a feature of liver failure, which is associated with increased risk of infection. The aims of the present study were to determine in vitro, in rats fed an ammoniagenic diet and in patients with cirrhosis, whether induction of hyperammonemia results in neutrophil dysfunction. As hyperammonemia produces cell swelling, we explored the role of the osmoregulating, p38 mitogen-activated protein kinase (p38 MAPK ) pathway in mediating this neutrophil dysfunction. Neutrophils were isolated from blood of healthy volunteers and incubated with either 75 M ammonia or phosphate-buffered saline. Both groups were studied under hyponatremic conditions and/or with the addition of p38 MAPK modulators. Neutrophil phagocytosis was measured in naive rats and rats fed an ammoniagenic diet and in patients with stable cirrhosis given placebo (n ‫؍‬ 8) or an amino acid solution inducing hyperammonemia (n ‫؍‬ 8). Cell volume and phagocytosis was analyzed by fluorescentactivated cell sorting using fluorescein isothiocyanate-labeled E. coli. p38 MAPK phosphorylation was measured by western blotting. In healthy neutrophils incubated with ammonia and in rats fed an ammoniagenic diet, neutrophils showed evidence of swelling, impaired phagocytosis, and increased spontaneous oxidative burst compared to controls. Phagocytosis was significantly impaired in patients with induced hyperammonemia compared to placebo. The effects of hyperammonemia and hyponatremia were synergistic. The p38 MAPK intracellular signaling pathways were activated in healthy neutrophils exposed to ammonia in association with increased burst activity. Neutrophil phagocytic dysfunction was abrogated by the addition of a p38 MAPK agonist. Conclusion: Ammonia produces neutrophil swelling and impairs neutrophil phagocytosis. The p38 MAPK intracellular signaling pathway has been shown to be important in mediating the ammonia-induced neutrophil dysfunction.

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“…7,8,10,30 Although the neuropathologic mechanism of decreased FA is not well-understood in the setting of cirrhosis, one possible explanation is demyelination. Osmotic demyelination (due to inappropriate correction of hyponatremia 31 ) has been noted in cirrhosis. 32 Moreover, central nervous system inflammation has been shown to play an important role in HE, 33 which may contribute to inflammatory demyelination as observed in other neurologic diseases such as multiple sclerosis.…”

Section: Results Of Gamma Analysismentioning

confidence: 99%