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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In advanced cirrhosis there is a reduction in the brain concentration of many organic osmolytes, particularly myo-inositol (MI). Hyponatremia could theoretically aggravate these changes as a result of hypo-osmolality of the extracellular fluid. The aim of this study was to determine the effects of hyponatremia on brain organic osmolytes and brain water content in cirrhosis. Brain organic osmolytes, measured by (1)H-magnetic resonance spectroscopy, and brain water content, as estimated by magnetization transfer ratio (MTR) and measurement of brain volume were determined in 14 patients with dilutional hyponatremia, 10 patients without hyponatremia, and eight healthy subjects. Patients with hyponatremia had remarkable lower levels of MI compared with values in nonhyponatremic patients and healthy subjects. Brain MI levels correlated directly with serum sodium and osmolality. Serum sodium was the only independent predictor of low brain MI levels. Serum sodium also correlated directly with other brain organic osmolytes, such as choline-containing compounds, creatine/phosphocreatine, and N-acetyl-aspartate. By contrast, brain glutamine/glutamate levels were higher in patients with cirrhosis compared with values in healthy subjects and correlated with plasma ammonia levels but not with serum sodium or osmolality. No significant differences were found in MTR values and cerebral volumes between patients with and without hyponatremia. In conclusion, dilutional hyponatremia in cirrhosis is associated with remarkable reductions in brain organic osmolytes that probably reflect compensatory osmoregulatory mechanisms against cell swelling triggered by a combination of high intracellular glutamine and low extracellular osmolality. These findings may be relevant to the pathogenesis of encephalopathy in hyponatremic patients.
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PMID:Effects of dilutional hyponatremia on brain organic osmolytes and water content in patients with cirrhosis. 1518 2

Background/Objectives: Magnetic resonance spectroscopic (MRS) studies have revealed abnormal metabolism in the brain of patients with liver cirrhosis, including an increase in total brain glutamine (Gln) and glutamate (Glu) levels (Glx). However, with conventional MRS techniques, it was difficult to separate the Glx signals. Using a high-magnetic field MR equipment and a newly developed data processing method, we attempted to separate the Glx signals on an MRS. Subjects and Methods: Twenty-three patients with liver cirrhosis and 11 healthy adults were enrolled in this study. After designating a region of interest in the occipital lobe gray matter of each subject, [Formula: see text] (proton)-MRS was performed using 3.0-T MR equipment. Results: MRS conducted using the 3.0-T MR equipment allowed Gln signals in the brain to be distinguished from the Glx signals. The brain signal intensity of Gln was found to be significantly higher in the liver cirrhosis group (0.658 +/- 0.23) than in the control group (0.473 +/- 0.08) (P < 0.05). Neither the Glu nor the Gln signal intensity showed any correlation with the blood ammonia level. Conclusion: High-magnetic field MRS allowed us to separate the Glx signals in the brain and revealed that the increase in the total brain Glu and Gln levels in patients is solely attributable to an increase in the level of Gln.
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PMID:Brain glutamine and glutamate levels in patients with liver cirrhosis: assessed by 3.0-T MRS. 1534 70

Minimal hepatic encephalopathy (MHE) is frequently diagnosed in patients with liver cirrhosis who do not show overt clinical cirrhosis-associated neurological deficits. This condition manifests primarily with visuo-motor and attention deficits. We studied the association between visuo-motor deficits and magnetic resonance spectroscopic parameters in cingulate grey matter and white matter of centrum semiovale in patients with liver cirrhosis. The data revealed an increase in the glutamate-glutamine/creatine ratio and a decrease in choline/creatine and inositol/creatine ratios in patients with liver cirrhosis. The analysis of the data showed that cirrhosis-associated deterioration of the visuo-motor function significantly correlates with a decrease in the choline/creatine ratio and an increase in N-acetylaspartate/choline in cingulate grey matter but not in the neighbouring white matter. Furthermore, the increase in the glutamate-glutamine/creatine ratio correlated significantly with the increase in the N-acetylaspartate/creatine ratio. These data suggest an association between altered choline, glutamate-glutamine and NAA metabolism in cingulate grey matter and symptoms of MHE, and underline the importance of differentiation between grey and white matter in magnetic resonance spectroscopic studies on patients with cirrhosis-associated brain dysfunction.
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PMID:Chemical shift magnetic resonance spectroscopy of cingulate grey matter in patients with minimal hepatic encephalopathy. 1565 60

Hepatic encephalopathy (HE) is a common problem in liver cirrhosis and is associated with typical changes of cerebral metabolite pattern observed by proton magnetic resonance spectroscopy (MRS). In HE, a reduction of the cerebral myo-inositol (mI) and choline (Cho) and an increase of glutamine/glutamate (Glx) can typically be detected with this method. In the present study MRS was used to assess prospectively specific parameters of cerebral metabolism before and after 6 days of treatment with a low-protein diet and with L-ornithine-L-aspartate (LOLA). 6 patients with liver cirrhosis were included in this pilot study. According to standardized neuropsychological tests overt HE or subclinical HE was detected in all patients. All patients received a low-protein diet (< 60 g/d) and were treated additionally with LOLA (20 g QD i. v.). MRS examinations were done before and after 6 days of treatment and the results were compared with those of healthy volunteers. Before treatment mI/Cr ratios in the grey matter were reduced significantly in cirrhotic patients as compared to healthy volunteers (0.30 +/- 0.22 vs. 0.68 +/- 0.11; P = 0.028). In addition, patients showed a (non-significant) reduction of the Cho/Cr-ratio (0.19 +/- 0.03 vs. 0.25 +/- 0.02; P = 0.17) and an elevated Glx/Cr-ratio (1.84 +/- 0.63 vs. 1.29 +/- 0.31; P = 0.05). After 6 days of treatment a significant increase of the Cho/Cr ratio (0.23 +/- 0.03 vs. 0.19 +/- 0.03; P = 0.028) was detectable and 5 of the 6 patients showed a (not significant) decrease of the elevated Glx/Cr ratios. After cessation of treatment an improvement in neuropsychological tests as shown by number-connection testing (P = 0.046) as well as a decrease of elevated pre-treatment ammonia blood levels were noted. These findings, however, did not correlate with the Child-Pugh classification or evidence of clinical/subclinical HE. Using (1)H-MRS it is possible to observe a specific pattern of cerebral metabolites in patients with overt and subclinical HE. In this pilot study a fast change of cerebral metabolite pattern after specific therapy of HE with LOLA was detected. Therefore, future studies with larger patient groups are needed to establish (1)H-MRS as an objective method for detection and treatment control in overt and subclinical HE, especially when compared to commonly used parameters such as ammonia levels or standardized neuropsychological tests.
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PMID:[Detection of subclinical and overt hepatic encephalopathy and treatment control after L-ornithine-L-aspartate medication by magnetic resonance spectroscopy ((1)H-MRS)]. 1583 Mar 3

Glutamine synthetase (GS) in the liver is restricted to a small perivenous hepatocyte population and plays an important role in the scavenging of ammonia that has escaped the periportal urea-synthesizing compartment. We examined the effect of a single intraperitoneal injection of lipopolysaccharide (LPS) in vivo on glutamine synthesis in rat liver. LPS injection induced expression of inducible nitric oxide synthase, which was maximal after 6 to 12 hours but returned toward control levels within 24 hours. Twenty-four hours after LPS injection, an approximately fivefold increase in tyrosine-nitrated proteins in liver was found, and GS protein expression was decreased by approximately 20%, whereas GS activity was lowered by 40% to 50%. GS was found to be tyrosine-nitrated in response to LPS, and immunodepletion of tyrosine-nitrated proteins decreased GS protein by approximately 50% but had no effect on GS activity. Together with the finding via mass spectrometry that peroxynitrite-induced inactivation of purified GS is associated with nitration of the active site tyrosine residue, our data suggest that tyrosine nitration critically contributes to inactivation of the enzyme. In line with GS inactivation, glutamine synthesis from ammonia (0.3 mmol/L) in perfused livers from 24-hour LPS-treated rats was decreased by approximately 50%, whereas urea synthesis was not significantly affected. In conclusion, LPS impairs hepatic ammonia detoxification by both downregulation of GS and its inactivation because of tyrosine nitration. The resulting defect of perivenous scavenger cell function with regard to ammonia elimination may contribute to sepsis-induced development of hyperammonemia in patients who have cirrhosis.
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PMID:Lipopolysaccharide-induced tyrosine nitration and inactivation of hepatic glutamine synthetase in the rat. 1584 46

Animal studies and results from 13N-ammonia positron emission tomography (PET) in patients with cirrhosis and minimal hepatic encephalopathy suggest that a disturbed brain ammonia metabolism plays a pivotal role in the pathogenesis of hepatic encephalopathy (HE). We studied brain ammonia kinetics in 8 patients with cirrhosis with an acute episode of clinically overt HE (I-IV), 7 patients with cirrhosis without HE, and 5 healthy subjects, using contemporary dynamic 13N-ammonia PET. Time courses were obtained of 13N-concentrations in cerebral cortex, basal ganglia, and cerebellum (PET-scans) as well as arterial 13N-ammonia, 13N-urea, and 13N-glutamine concentrations (blood samples) after 13N-ammonia injection. Regional 13N-ammonia kinetics was calculated by non-linear fitting of a physiological model of brain ammonia metabolism to the data. Mean permeability-surface area product of 13N-ammonia transfer across blood-brain barrier in cortex, PS(BBB), was 0.21 mL blood/min/mL tissue in patients with HE, 0.31 in patients without HE, and 0.34 in healthy controls; similar differences were seen in basal ganglia and cerebellum. Metabolic trapping of blood 13N-ammonia in the brain showed neither regional, nor patient group differences. Mean net metabolic flux of ammonia from blood into intracellular glutamine in the cortex was 13.4 micromol/min/L tissue in patients with cirrhosis with HE, 7.4 in patients without HE, and 2.6 in healthy controls, significantly correlated to blood ammonia. In conclusion, increased cerebral trapping of ammonia in patients with cirrhosis with acute HE was primarily attributable to increased blood ammonia and to a minor extent to changed ammonia kinetics in the brain.
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PMID:Brain metabolism of 13N-ammonia during acute hepatic encephalopathy in cirrhosis measured by positron emission tomography. 1700 43

Hepatic encephalopathy can arise from portal-systemic shunting in the absence of intrinsic liver disease. However, there are few descriptions of this form of encephalopathy. Portal vein thrombosis is an infrequent disease that causes portal-systemic shunting. Episodic hepatic encephalopathy has been described in patients with portal vein thrombosis, but it is not known if these patients develop minimal hepatic encephalopathy. We designed a study to investigate the neurological consequences of portal vein thrombosis in patients without cirrhosis and no clinical signs of encephalopathy. For this purpose, 10 patients underwent neuropsychological tests, an oral glutamine challenge test, and brain magnetic resonance (MR) imaging. The results were compared with those obtained in 10 healthy controls. Patients with portal vein thrombosis exhibited abnormalities in the results of neuropsychological tests, oral glutamine challenge test, and MR similar to those described in hepatic encephalopathy associated with cirrhosis. MR spectroscopy revealed a decrease in myo-inositol and an increase in glutamine. The increase in glutamine correlated with an increase in ammonia following the oral glutamine challenge test, signs of increased brain water (decrease in magnetization transfer ratio), and impairment of attention tests. In conclusion, patients with noncirrhotic portal vein thrombosis develop subclinical neurological abnormalities compatible with minimal hepatic encephalopathy. These disturbances, which include signs of increase in brain water and a compensatory osmotic response (decrease in brain myo-inositol), appear to be secondary to brain exposure to ammonia induced by portal-systemic shunting.
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PMID:Noncirrhotic portal vein thrombosis exhibits neuropsychological and MR changes consistent with minimal hepatic encephalopathy. 1655 41

Studies of the pathogenesis of hepatic encephalopathy are hampered by the lack of a satisfactory animal model. We examined the neurological features of rats after bile duct ligation fed a hyperammonemic diet (BDL+HD). Six groups were studied: sham, sham pair-fed, hyperammonemic, bile duct ligation (BDL), BDL pair fed, and BDL+HD. The BDL+HD rats were made hyperammonemic via an ammonia-containing diet that began 2 weeks after operation. One week later, the animals were sacrificed. BDL+HD rats displayed an increased level of cerebral ammonia and neuroanatomical characteristics of hepatic encephalopathy (HE), including the presence of type II Alzheimer astrocytes. Both BDL and BDL+HD rats showed activation of the inflammatory system. BDL+HD rats showed an increased amount of brain glutamine, a decreased amount of brain myo-inositol, and a significant increase in the level of brain water. In coordination tests, BDL+HD rats showed severe impairment of motor activity and performance as opposed to BDL rats, whose results seemed only mildly affected. In conclusion, the BDL+HD rats displayed similar neuroanatomical and neurochemical characteristics to human HE in liver cirrhosis. Brain edema and inflammatory activation can be detected under these circumstances.
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PMID:Brain edema and inflammatory activation in bile duct ligated rats with diet-induced hyperammonemia: A model of hepatic encephalopathy in cirrhosis. 1672 29

The term hepatic encephalopathy encompasses a spectrum of neuropsychiatric abnormalities seen in patients with liver dysfunction. Distinct syndromes are identified in acute liver failure and cirrhosis. Rapid deterioration in consciousness level and increased intracranial pressure that may result in brain herniation and death are a feature of acute liver failure whereas manifestations of hepatic encephalopathy in cirrhosis include psychomotor dysfunction, impaired memory, increased reaction time, sensory abnormalities, poor concentration and in severe forms, coma. In patients with acute-on-chronic liver failure the pathophysiology remains undefined. Ammonia has been considered central to its pathogenesis. In the brain, the astrocyte is the main site for ammonia detoxification, during the conversion of glutamate to glutamine. An increased ammonia level raises the amount of glutamine within astrocytes, causing an osmotic imbalance resulting in cell swelling and ultimately brain oedema. Recent studies suggest that inflammation and it modulators may play a synergistic role with ammonia in the pathogenesis of hepatic encephalopathy. Therapy of hepatic encephalopathy is directed primarily at reducing ammonia generation and increasing its detoxification. The currently accepted regimens to treat hepatic encephalopathy such as lactulose and protein restricted diets need further clinical trials and therefore placebo controlled clinical trials in hepatic encephalopathy are justified. In liver failure, ammonia metabolism involves multiple organs and therefore ammonia reduction will require simultaneous targeting of these organs. The present review describes the pathophysiological basis of hepatic encephalopathy and evaluates the available therapies.
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PMID:Management of hepatic encephalopathy in patients with cirrhosis. 1722 99

Hepatic encephalopathy (HE) is a common neuropsychiatric complication of liver disease affecting about 20-30% patients with cirrhosis. HE may only affect quality of life (e.g. impairments in attention; coordination; driving ability), but in some patients this progresses to coma and death; defining mortality in those with acute liver failure. HE is thought to occur through accumulation of ammonia as a by-product of protein metabolism. In liver failure ammonia accumulates to toxic levels, resulting in ammonia-associated brain swelling. Presently, there is no proven therapy for HE though recent studies suggest that during liver failure, ammonia removal by skeletal muscle (by conversion to glutamine) can be manipulated; also that ammonia and amino acid metabolism should be viewed in terms of their interorgan relationship. This led us to develop a novel concept for ammonia removal. Preliminary studies provide the proof of concept that the combination of L-ornithine (amino acid) with phenylactetate, as L-ornithine phenylacetate (OP), reduces toxic levels of ammonia by (1) L-ornithine acting as a substrate for glutamine synthesis from ammonia in skeletal muscle and (2) phenylacetate excreting the ornithine-related glutamine as phenylacetylglutamine in the kidneys. As both L-ornithine and phenylacetate are already available for human use, data showing its usefulness in ammonia lowering could translate quickly into providing the much needed therapy for HE patients.
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PMID:L-Ornithine phenylacetate (OP): a novel treatment for hyperammonemia and hepatic encephalopathy. 1746 90


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