UMLS:C0023890 - FACTA Search

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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

Hyperammonemia is the main responsible for the neurological alterations in hepatic encephalopathy in patients with liver failure. We studied the function of the glutamate-nitric oxide (NO)-cGMP pathway in brain in animal models of hyperammonemia and liver failure and in patients died with liver cirrhosis. Activation of glutamate receptors increases intracellular calcium that binds to calmodulin and activates neuronal nitric oxide synthase, increasing nitric oxide, which activates soluble guanylate cyclase (sGC), increasing cGMP. This glutamate-NO-cGMP pathway modulates cerebral processes such as circadian rhythms, the sleep-waking cycle, and some forms of learning and memory. These processes are impaired in patients with hepatic encephalopathy. Activation of sGC by NO is significantly increased in cerebral cortex and significantly reduced in cerebellum from cirrhotic patients died in hepatic coma. Portacaval anastomosis in rats, an animal model of liver failure, reproduces the effects of liver failure on modulation of sGC by NO both in cerebral cortex and cerebellum. In vivo brain microdialisis studies showed that sGC activation by NO is also reduced in vivo in cerebellum in hyperammonemic rats with or without liver failure. The content of alpha but not beta subunits of sGC are increased both in frontal cortex and cerebellum from patients died due to liver disease and from rats with portacaval anastomosis. We assessed whether determination of activation of sGC by NO-generating agent SNAP in lymphocytes could serve as a peripheral marker for the impairment of sGC activation by NO in brain. Chronic hyperammonemia and liver failure also alter sGC activation by NO in lymphocytes from rats or patients. These findings show that the content and modulation by NO of sGC are strongly altered in brain of patients with liver disease. These alterations could be responsible for some of the neurological alterations in hepatic encephalopathy such as sleep disturbances and cognitive impairment.
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PMID:Alterations in soluble guanylate cyclase content and modulation by nitric oxide in liver disease. 1531 89

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

Chronic alcoholism leads to localized brain damage, which is prominent in superior frontal cortex but mild in motor cortex. The likelihood of developing alcohol dependence is associated with genetic markers. GABAA receptor expression differs between alcoholics and controls, whereas glutamate receptor differences are muted. We determined whether genotype differentiated the localized expression of glutamate and gamma-aminobutyric acid (GABA) receptors to influence the severity of alcohol-induced brain damage. Cerebrocortical tissue was obtained at autopsy from alcoholics without alcohol-related disease, alcoholics with cirrhosis, and matched controls. DRD2A, DRD2B, GABB2, EAAT2, and 5HTT genotypes did not divide alcoholic cases and controls on N-methyl-d-aspartate (NMDA) receptor parameters. In contrast, alcohol dehydrogenase (ADH)3 genotype interacted significantly with NMDA receptor efficacy and affinity in a region-specific manner. EAAT2 genotype interacted significantly with local GABAA receptor beta subunit mRNA expression, and GABB2 and DRD2B genotypes with beta subunit isoform protein expression. Genotype may modulate amino acid transmission locally so as to mediate neuronal vulnerability. This has implications for the effectiveness of pharmacological interventions aimed at ameliorating brain damage and, possibly, dependence.
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PMID:Genes and gene expression in the brain of the alcoholic. 1534 66

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

Hepatic encephalopathy (HE) is a neuropsychiatric syndrome, which develops in patients with acute or chronic liver failure. It is widely accepted to be due to impairment of hepatic clearance of toxic products from the gut such as ammonia. Accumulation of ammonia induces a glutamate neurotoxicity leading to an increased tone of the gamma-aminobutyric acid A (GABA-A) receptor system in the brain which results in HE. Factors either increasing the ammonia levels (protein load, constipation, sepsis, or gastrointestinal bleeding) or potentiating the functional activity of the GABAergic system [natural benzodiazepine-like compounds (NBZDs) or exogenous benzodiazepines] may act as precipitating factors of HE. NBZDs are present in trace amounts in the blood of normal subjects and have been found to be increased in the blood of patients with liver cirrhosis, with or without HE. These compounds may derive either from the diet since they have been found in plants, vegetables and animals or from gut bacteria. The observation that intestinal bacterial flora is involved in the production of both primary agent of HE (ammonia) and precipitating factors (NBZDs) suggests that the use of nonabsorbable antibiotics such as rifaximin may be useful in preventing episodes of HE in patients with liver cirrhosis.
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PMID:Management of hepatic encephalopathy: role of rifaximin. 1585 52

Branched-chain amino acids (BCAA: leucine, isoleucine and valine) are not just structural constituents of proteins, but have ''pharmacologic'' properties, known for several years: BCAA are catabolized mainly in muscle; can be oxidized with energy production, being nitrogen donors for other amino acids; regulate protein synthesis and degradation; modulate metabolism of neuroactive mediators. These properties make the clinical use of BCAA particularly suitable in critical conditions such as liver cirrhosis, sepsis, surgical or nonsurgical trauma, acute renal failure, acute pancreatitis, cancer, in which energy production from conventional substrates is altered and, at the same time, reduction of protein catabolism and enhancement of synthetic processes is advisable. Recently, the changes of plasma aminoacidograms induced by the administration of high-dose BCAA in sepsis have been better detailed: 1) a tendency to normalization of high levels of proline and of other amino acids transported intracellularly by transport system ''A''; 2) less relevant reduction of the levels of other amino acids; 3) increase of the levels of taurine, glutamate and aspartate; more complex interactions with specific amino acids. These changes, and changes of other variables, reconfirm in part some well-known properties of BCAA, and are also objective indicators of an improvement of the metabolic abnormalities of sepsis induced by BCAA administration. In sepsis and in other stress conditions it is recommended to administer, within balanced parenteral nutritional regimens, AA solutions with a 35-50% BCAA concentration.
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PMID:[The branched-chain amino acids]. 1650 46

Hepatic encephalopathy is a complex neuropsychiatric syndrome present in patients with liver disease that includes impaired intellectual function and alterations in personality and neuromuscular coordination. Hyperammonemia and liver failure result in altered glutamatergic neurotransmission, which contributes to hepatic encephalopathy. Alterations in the function of the glutamate-nitric oxide-cGMP pathway may be responsible for some of the neurological alterations found in hepatic encephalopathy. The function of this pathway is altered in brain from patients died with liver cirrhosis and one altered step of the pathway is the activation of soluble guanylate cyclase by nitric oxide, which is increased in cerebral cortex and reduced in cerebellum from these patients. Portacaval anastomosis and bile duct ligation plus hyperammonemia in rats reproduce the alterations in the activation of soluble guanylate cyclase by NO both in cerebellum and cerebral cortex. We assessed whether hyperammonemia is responsible for the region-selective alterations in guanylate cyclase modulation in liver cirrhosis and whether the alteration occurs in neurons or in astrocytes. Activation of guanylate cyclase by nitric oxide is lower in cerebellar neurons exposed to ammonia (1.5-fold) than in control neurons (3.3-fold). The activation of guanylate cyclase by nitric oxide is higher in cortical neurons exposed to ammonia (8.7-fold) than in control neurons (5.5-fold). The activation is not affected in cerebellar or cortical astrocytes. These findings indicate that hyperammonemia is responsible for the differential alterations in the modulation of soluble guanylate cyclase by nitric oxide in cerebellum and cerebral cortex of cirrhotic patients. Moreover, under the conditions used, the alterations occur selectively in neurons and not in astrocytes.
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PMID:Brain regional alterations in the modulation of the glutamate-nitric oxide-cGMP pathway in liver cirrhosis. Role of hyperammonemia and cell types involved. 1651 21

Hepatitis C virus is a major global health problem affecting an estimated 170 million people worldwide. Chronic infection is common and can lead to cirrhosis and liver cancer. There is no vaccine available and current therapies have met with limited success. The viral RNA genome encodes a polyprotein that includes two proteases essential for virus replication. The NS2-3 protease mediates a single cleavage at the NS2/NS3 junction, whereas the NS3-4A protease cleaves at four downstream sites in the polyprotein. NS3-4A is characterized as a serine protease with a chymotrypsin-like fold, but the enzymatic mechanism of the NS2-3 protease remains unresolved. Here we report the crystal structure of the catalytic domain of the NS2-3 protease at 2.3 A resolution. The structure reveals a dimeric cysteine protease with two composite active sites. For each active site, the catalytic histidine and glutamate residues are contributed by one monomer, and the nucleophilic cysteine by the other. The carboxy-terminal residues remain coordinated in the two active sites, predicting an inactive post-cleavage form. Proteolysis through formation of a composite active site occurs in the context of the viral polyprotein expressed in mammalian cells. These features offer unexpected insights into polyprotein processing by hepatitis C virus and new opportunities for antiviral drug design.
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PMID:Structure of the catalytic domain of the hepatitis C virus NS2-3 protease. 1713 77

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