Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0023890 (cirrhosis)
 42,195 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To date, no attempt has been made to study alterations occurring in the amino acid profile in chronic models of thioacetamide-induced liver cirrhosis. In this work, changes in serum amino acids and proteins in rats with thioacetamide-induced liver cirrhosis are reported, together with changes in enzyme activities in the liver and serum. Seventeen female Wistar rats were used. Eight rats were given 300 mg thioacetamide/l in drinking water for 4 months and nine rats were given water ad libitum during the same time-period. Significant increases in glycine, alanine, serine, methionine, glutamate, ornithine, phenylalanine, tyrosine, histidine and proline were observed in rats with the resulting experimental liver cirrhosis. Threonine, taurine, glutamine, lysine and citrulline tended to increase while isoleucine, leucine, aspartate, arginine and tryptophan tended to decrease. Total and nonessential amino acids increased significantly in cirrhotic animals. Total essential and aromatic amino acids tended to increase in the thioacetamide-treated group, whereas branched chain amino acids tended to decrease in the same group. Regarding serum proteins, a decrease in albumin concentration in the thioacetamide-treated animals was the only change detected. The liver enzyme activities under observation (aspartate and alanine aminotransferases, glutamate dehydrogenase and threonine deaminase) were lower in the thioacetamide group. Decreases were significant for both transaminases and threonine deaminase. Results for serum activities showed that transaminases did not change in thioacetamide-treated rats in comparison with controls. In contrast, alkaline phosphatase rose dramatically in cirrhotic rats. We conclude that the serum amino acid pattern in this chronic model of liver cirrhosis resembles in part that of the corresponding human disease.
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PMID:Serum amino acid changes in rats with thioacetamide-induced liver cirrhosis. 857 92

This paper evaluates the role of decreased food intake in protein metabolism in cirrhotic animals by comparing the changes with those observed in pair-fed controls. Rats were injected with [14C]leucine and then divided into 3 groups. Liver cirrhosis was induced in 1 group of rats by repeated intragastric administration of CCl4 in oil over a period of 8 weeks. Control animals were gavaged with oil and either pair-fed or given access to food ad libitum. Three days after the last intragastric dose, rats were injected with [3H]leucine and sacrificed 20 min later. The daily food intake of CCl4 rats declined to 60% of that of the ad libitum controls. Both the pair-fed control group and the cirrhotic group showed decreased body weight gain, and a decline in muscle and intestinal protein degradation. The pair-fed and the cirrhotic groups differed from one another in many metabolic abnormalities. In the cirrhotic group we observed higher levels of serine, asparagine, proline, methionine, tyrosine, phenylalanine, ornithine and histidine, and lower levels of valine, isoleucine and arginine. In these animals higher relative (per kilogram body weight) weights and protein content of the spleen, kidneys and heart were observed. Additionally higher liver weight despite lower protein concentration, as well as lower liver protein degradation and lower skeletal muscle protein synthesis were found.
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PMID:Protein metabolism in cirrhotic rats: effect of dietary restriction. 867 70

Albumin and fibrinogen synthesis rates were measured in 15 subjects with different clinical stages of postviral cirrhosis and compared with galactose elimination capacity and aminopyrin breath test. Forty-three mg per kg body weight [2H5ring]phenylalanine with an isotopic enrichment of 10 atom% were intravenously injected. [2H5ring]phenylalanine enrichments in the plasma-free phenylalanine and the albumin and fibrinogen isolates were measured by gas chromatography-mass spectrometry. Fractional synthesis rates of albumin were normal in Child A cirrhosis (7.6 +/- 2.2%d), but were lower in both Child B (3.5 +/- 0.8%d) and C (4.5 +/- 2.8%d). Absolute rates of albumin synthesis were (103 +/- 30 mg/kg/d) in the child A group and substantially lower in the Child B (50 +/- 3 mg/kg/d) and C (36 +/- 20 mg/kg/d) group. The average fractional synthesis rate of fibrinogen was 16.7 +/- 7.5%d and the absolute synthesis rate 11.6 +/- 6.4 mg/kg/d. The values of the galactose elimination capacity and the aminopyrin breath test were below the normal range in all patients, gradually decreasing with an increase in the severity of the clinical stage of cirrhosis. Albumin synthesis rates significantly correlated with the Child scores, the galactose elimination capacity, and the aminopyrin breath test, whereas fibrinogen synthesis rates showed no such correlations.
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PMID:Albumin but not fibrinogen synthesis correlates with galactose elimination capacity in patients with cirrhosis of the liver. 870 82

Since plasma is generally employed for amino acid analysis, we compared amino acid levels in plasma with those in serum for healthy individuals and examined the influence of separation and storage conditions on the stability of the samples. Then, we determined the amino acid levels of frozen serum samples obtained from sarin poisoned patients. A. Comparison of Amino Acid Levels in Plasma and Those in Serum Blood was collected from 5 healthy individuals. Then, heparinated plasma and serum were separated by centrifugation immediately after blood collection. Serum was also separated by centrifugation after standing whole blood at room temperature for 1 hour. Frozen plasma and serum were store at -40 degrees C for 5 months. All were subjected to analysis in an amino acid analyzer. It was found that the cystine (Cys) and 3-methyl-histidine (3-M-His) levels in serum and plasma were affected when stored in a frozen state, that the aspartate (Asp) level was changed according to the method of collecting serum, and that the taurine (Tau) and ornithine (Orn) levels were affected by standing blood. B. Analysis of Blood Taken from Sarin Poisoned Patients Twelve sarin poisoned patients were selected as subjects, and serum cholinesterase (Ch-E) and serum albumin (Alb) levels were determined. Amino acid analysis was conducted using an amino acid analyzer. Serum samples which had been obtained from the 6 patients and frozen and stored at -40 degrees C from 5 months were used for amino acid analysis. As a result, the serum Ch-E level decreased and the Alb level tended to rise. Since the Ch-E/Alb ratio was reduced in the sarin poisoned patients, it is considered useful for discrimination from liver cirrhosis in which both Ch-E and Alb levels decreased. Amino acid levels in the serum obtained from the sarin poisoned patients were compared with those of healthy individuals, both of which had been stored under the same conditions. There were significant differences in Asp, glutamate (Glu), phenylalanine (Phe), 3-M-His, glutamine (Gln), and Cys levels. The Glu, Phe, and Gln levels were not affected by storage of serum in a frozen state, while the Glu and Phe levels were elevated and the Gln level was reduced. Although Cys exhibited lower values in frozen serum samples, the Cys level was elevated with a rise in the serum Ch-E levels. Therefore, we deduced that Cys metabolism disorders also occur in sarin poisoning. As stated above, the Glu and Phe levels were elevated and the Gln and Cys levels were reduced, suggesting the presence of abnormal amino acid metabolism, in patients with sarin-poisoning.
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PMID:[Blood amino acid levels in sarin poisoning patients]. 928 31

Breath tests using 13C-labelled substrates require the measurement of 13CO2/12CO2 ratio in breath gas samples. Next to isotope ratio mass spectrometry (IRMS), which is very sensitive but also complex and expensive, alternatively isotope selective nondispersive infrared spectrometry (NDIRS) can be used to determine the 13CO2/12CO2 ratio in expired breath. In this study we compared NDIRS- with IRMS-results to investigate whether the less expensive and very simply to operate NDIRS works as reliable as IRMS. For this purpose we applicated 1- 13C-Phenylalanine to patients with advanced liver cirrhosis and healthy volunteers and took duplicated breath samples for IRMS and NDIRS at selected time points. Our data show a good correlation between these two methods for a small number of samples as required for simple breath tests. Longer series, where repeated measurements are required on the NDIRS instrument lead to a decreasing correlation. This indicates the superiority of IRMS concerning 13CO2-kinetics over longer time periods.
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PMID:Determination of 13CO2/12CO2 ratio by IRMS and NDIRS. 985 49

Alpha1-antitrypsin (alpha1AT) deficiency is an autosomal recessive disorder that can cause pulmonary emphysema and liver disease. We report here the case of a 59-year-old woman who was admitted to hospital for evaluation of jaundice. She had no history of hepatitis or childhood liver disease. She had never received a blood transfusion, nor had she abused drugs or alcohol. Transjugular liver biopsy was then performed and revealed a micronodular cirrhosis. Ten months later, because of persistent liver cell failure and ascites, she underwent an orthotopic liver transplantation. Investigation of alpha1AT system in the proband revealed a substantial decrease in serum alpha1AT associated with a low elastase inhibitory capacity. The Pi phenotype revealed a PiM-like profile. Sequencing of exons 1-5 demonstrated the presence of the M3 allele. Moreover, a triple nucleotide deletion was detected in exon 2 of one allele. This caused an "in-phase" frameshift, coding for a protein deficient in a single Phe residue, which corresponded to the Mmalton variant. After liver biopsy, periodic acid-Schiff-positive acidophilic bodies resistant to diastase digestion were observed in the cytoplasm of hepatocytes. These results demonstrated that our patient had a heterozygous M3Mmalton alpha1AT genotype related to a deficiency phenotype. This observation is the first of a patient with heterozygous Mmalton genotype associated with an alpha1AT deficiency that induced severe liver disease requiring orthotopic liver transplantation.
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PMID:Heterozygous M3Mmalton alpha1-antitrypsin deficiency associated with end-stage liver disease: case report and review. 1146 49

To evaluate the alteration of cerebral blood flow and oxygen metabolism in cirrhosis, we measured regional cerebral blood flow (rCBF), cerebral metabolic rate for oxygen (rCMRO2), and oxygen extraction fraction (rOEF) in twelve patients with cirrhosis (six with a history of hepatic encephalopathy and six without) and six age-matched controls using positron emission tomography. Regional CBF in whole brain was not different in cirrhotic patients from that in controls. In six cirrhotic patients with a history of hepatic encephalopathy, rCMRO2 was significantly lower in the frontal, temporal, parietal and occipital cortices, hippocampus, thalamus, cerebellum and brain stem, than that in each region of controls. On the other hand, rCMRO2 in six cirrhotic patients without a history of hepatic encephalopathy did not differ from the controls in all regions except for the frontal cortex. Regional OEF in cirrhotic patients without a history of hepatic encephalopathy was higher in the hippocampus and striatum than that in each region of controls. Among twelve cirrhotic patients, rCMRO2 in the occipital cortex and striatum correlated directly with plasma leucine levels, and rCMRO2 in the striatum directly correlated with plasma valine levels. Regional CMRO2 in the frontal cortex, temporal cortex, parietal cortex, white matter as well as brain stem correlated inversely with plasma phenylalanine levels, and rCMRO2 in the occipital cortex correlated inversely with plasma tyrosine levels. Brain oxygen metabolism is impaired in cirrhotic patients with a history of hepatic encephalopathy, but preserved in those without a history or in the early stage of cirrhosis. Reduced oxygen metabolism is related with altered amino acid metabolism.
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PMID:Alteration of regional cerebral metabolism in patients with cirrhosis in positron emission tomography. 1158 15

Liver disease is associated with an abnormal elevation of the plasma concentrations of the aromatic amino acids phenylalanine and tyrosine. The liver is the main site of aromatic amino acid metabolism, particularly the hydroxylation of phenylalanine to tyrosine and further tyrosine degradation. In the present study, we have examined the usefulness of the L-[1-13C]phenylalanine breath test (13C-PheBT) and L-[13C]tyrosine breath test (13C-TyrBT) for the detection of hepatic damage in patients with liver cirrhosis. First, the time courses of 13CO2 excretion after the administration of L-[1-13C]phenylalanine and L-[1-13C]tyrosine were compared. The peak times (the time expressed in minutes at which 13CO2 excretion was maximal) were 20 min in both breath tests, but 13C-TyrBT gave a higher peak than 13C-PheBT. Next, the parameters of 13C-PheBT and 13C-TyrBT were compared with biochemical liver function test values. These parameters were well correlated with several liver blood test values conventionally regarded as measures of hepatocyte functional reserve. Therefore, 13C-PheBT and 13C-TyrBT may be useful to assess the degree and progression of hepatic dysfunction.
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PMID:Evaluation of 13C-phenylalanine and 13C-tyrosine breath tests for the measurement of hepatocyte functional capacity in patients with liver cirrhosis. 1176 66

Increased GABA-mediated neurotransmission, reported to occur in hepatic encephalopathy (HE), is associated with a decrease in the release of Met-enkephalin and the expression of its coding gene in the brain. Furthermore, patients with cirrhosis and a history of HE exhibit increased sensitivity to the neuroinhibitory effects of morphine. Thus, there is a rationale to study the status of the endogenous opioid system in HE. The aim of this study was to determine whether mu-opioid receptors in the brain are up-regulated in a well characterized model of HE. Binding parameters of mu-opioid receptors were derived by assaying the binding of the opiate agonist [3H]-tyr-D-Ala-Gly-N-Methyl-Phe-Gly-ol (DAMGO) to brain membranes from rats with precisely defined stages of HE and control animals. The mean density of mu-opioid receptor sites (Bmax) in rats with stage II, III, and IV HE was 15, 29, and 33% higher, respectively, than the corresponding control value (p<0.01). In addition, the affinity of mu opioid receptors for the agonist (1/Kd) also increased with progression of HE (mean for stage IV HE vs. corresponding control mean, p<0.01). In conclusion, in liver failure, increased density and affinity of central mu-opioid receptors in the brain may: (i) be the basis for the documented increased sensitivity to opiate agonists; and (ii) occur as a consequence of increased GABAergic tone reducing neuronal synthesis and release of opioid agonist peptides.
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PMID:Up-regulation of central mu-opioid receptors in a model of hepatic encephalopathy: a potential mechanism for increased sensitivity to morphine in liver failure. 1199 Dec 57

Conformational diseases are caused by a structural rearrangement within a protein that results in aberrant intermolecular linkage and tissue deposition. This is typified by the polymers that form with the Z deficiency variant of alpha 1-antitrypsin (Glu-342 --> Lys). These polymers are retained within hepatocytes to form inclusions that are associated with hepatitis, cirrhosis, and hepatocellular carcinoma. We have assessed a surface hydrophobic cavity in alpha1-antitrypsin as a potential target for rational drug design in order to prevent polymer formation and the associated liver disease. The introduction of either Thr-114 --> Phe or Gly-117 --> Phe on strand 2 of beta-sheet A within this cavity significantly raised the melting temperature and retarded polymer formation. Conversely, Leu-100 --> Phe on helix D accelerated polymer formation, but this effect was abrogated by the addition of Thr-114 --> Phe. None of these mutations affected the inhibitory activity of alpha 1-antitrypsin. The importance of these observations was underscored by the finding that the Thr-114 --> Phe mutation reduced polymer formation and increased the secretion of Z alpha 1-antitrypsin from a Xenopus oocyte expression system. Moreover cysteine mutants within the hydrophobic pocket were able to bind a range of fluorophores illustrating the accessibility of the cavity to external agents. These results demonstrate the importance of this cavity as a site for drug design to ameliorate polymerization and prevent the associated conformational disease.
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PMID:Targeting a surface cavity of alpha 1-antitrypsin to prevent conformational disease. 1280 89


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