Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Lamivudine therapy for chronic hepatitis and decompensated liver cirrhosis related to the hepatitis B virus (HBV) resulted in improvement of liver function and inhibition of viral replication. Despite emergence of the HBV mutant, e-antigen seroconversion and improvement of liver function may be achieved with continuation of lamivudine therapy. Although hepatic decompensation has been reported in a few cases after the emergence of lamivudine-resistant mutants, fatal cases of non-transplant patients have only rarely been reported in the literature. Here, we describe a patient with HBV-related liver cirrhosis who died after a breakthrough infection with a lamivudine-resistant mutant. Hepatic failure and mortality developed after flare-up of severe hepatitis after 13 months of lamivudine treatment. Emergence of the HBV mutant with substitution of isoleucine for leucine at residue 426 (L4261) in combination with isoleucine for methionine at residue 550 (M5501) was observed at 10 and 13 months of treatment.
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PMID:Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis. 1191 2

Entire nucleotide sequences of the HBV genome typical for various stages of HBV carriers are currently unknown. Comparison between conserved sequences in HBeAg-positive asymptomatic carriers (HBeAg ASCs) and mutations characteristic for HBeAb-positive asymptomatic carriers (HBeAb ASCs) are of clinical importance. In this study, we determined the entire nucleotide sequences of the HBV genome of patients infected with genotype C (HBeAg ASCs, 11 cases; HBeAb ASCs, seven cases; patients with liver cirrhosis (LC), five cases). Mutations in the entire nucleotide sequences were found more frequently in HBeAb ASCs than in HBeAg ASCs. In the precore/core (preC/C) region, amino acid mutations were more frequent in HBeAb ASCs (3.03%) than in HBeAg ASCs (0.00%) and patients with LC (0.69%). It was suggested that the mutations in the preC/C region had a close relationship with clinical status of HBV carriers. Mutations of leucine to isoleucine at a.a. 100 of the core region and of threonine to serine at a.a. 340 of the polymerase region were found frequently in HBeAb ASCs. In patients with LC, it was suggested that defective interfering particles (DI particles) play a role in the progression of stages. We conclude that attention should be given to mutations at a.a. 340 of the polymerase protein in addition to core protein.
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PMID:Analysis of the entire nucleotide sequence of hepatitis B virus: characteristics of HBeAg-positive asymptomatic carriers, HBeAb positive asymptomatic carriers and patients with liver cirrhosis. 1219 73

This study tests the hypothesis that administration of an oral amino acid load mimicking hemoglobin in patients with cirrhosis of the liver causes deterioration in neuropsychological function and a reduction in regional cerebral perfusion. Eight overnight fasted, metabolically stable cirrhotic patients with no evidence of overt hepatic encephalopathy were studied prior to and 4 h after simulating an upper gastrointestinal bleed by oral administration of 75 g of a solution mimicking the amino acid composition of hemoglobin. Neuropsychological function was measured using a test battery. Peripheral venous blood was collected for the measurement of ammonia and amino acid concentrations. Regional cerebral perfusion was measured using a head SPECT scanner following intravenous administration of technetium-99m hexamethyl propylamineoxime. The amino acid solution resulted in significant deterioration in the immediate and delayed story recall tests. Ammonia concentration increased from a median of 87 (range 67-94) micromol/L to 105 (98-112) micromol/L at 4 h after the simulated bleed (p < 0.01). The concentration of almost all amino acids increased; only isoleucine levels decreased following the upper gastrointestinal bleed. SPECT analysis showed a significant reduction in cerebral perfusion after the simulated bleed in both temporal lobes, left superior frontal gyrus, and right parietal and cingulate gyrus. An oral amino acid load mimicking hemoglobin in cirrhotic patients produces hyperammonemia and hypoisoleucinemia and causes a significant deterioration in memory tests, probably due to a reduction in regional cerebral perfusion. The model of simulating the metabolic effects of an upper gastrointestinal bleed in patients with cirrhosis of the liver seems to be useful in studying the metabolism of hepatic encephalopathy.
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PMID:Oral amino acid load mimicking hemoglobin results in reduced regional cerebral perfusion and deterioration in memory tests in patients with cirrhosis of the liver. 1260 81

Branched-chain amino acid (BCAA: Leu, Ile, and Val) mixture has been used for treatment of hypoalbuminemia in patients with decompensated liver cirrhosis in Japan. It has been known that BCAA, especially leucine, activates mTOR signals and inhibition of protein degradation results in promoting protein synthesis in vitro. Furthermore, leucine activates glycogen synthase via mTOR signals in L6 cell, but not hepatocyte, and it has been shown that leucine improved glucose metabolism in normal and cirrhosis model rats. In this review, it will be proposed about the pharmacological activity of branched-chain amino acids, mainly leucine, on tissue specificity of cirrhotic disease.
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PMID:Pharmacological activities of branched-chain amino acids: specificity of tissue and signal transduction. 1468 73

The Z variant of alpha1-antitrypsin (Z-AT) is present in 4% of Northern Europeans and is associated with liver cirrhosis and emphysema. Polymers accumulate within the hepatocyte and the subsequent plasma deficiency of AT renders the lungs susceptible to proteolysis and early onset emphysema. We have previously demonstrated that the Phe-Leu-Glu-Ala-Ile-Gly (6 mer) peptide specifically binds to Z-AT and inhibits polymerization. Here we present the first detailed biochemical study of the purified Z-AT-6 mer binary complex. Biochemical studies indicated that this complex was inactive as a proteinase inhibitor and the peptide annealed to beta-sheet A of Z-AT. Removal of the N-acetyl terminus of the 6 mer peptide did not affect the peptide's ability to prevent polymer formation. However, the nonacetylated 6 mer-Z-AT complex dissociated at a rate 2.75 x faster than the acetylated 6 mer-Z-AT complex to yield an active inhibitor; Koff 5.5 +/- 1.07 versus 2.0 +/- 0.25 10(6) s(-1), respectively. These biochemical data indicate a potential therapeutic approach whereby polymerization is prevented in the liver, with the gradual release of the peptide from the binary complex restoring proteinase inhibitory function within the tissues. Thus, it raises the novel prospect of ameliorating both the cirrhosis and the emphysema associated with Z-AT.
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PMID:Inhibiting polymerization: new therapeutic strategies for Z alpha1-antitrypsin-related emphysema. 1501 19

We investigated glutathione S-transferase (GST) P1 Ile (105) Val, T1, and M1 polymorphisms in 45 patients with documented cryptogenic cirrhosis and 56 healthy control subjects. Polymerase chain reaction-based procedures were performed in the studied populations to confirm the genotypes of GSTT1, M1, and P1. Ile/Val and Val/Val GSTP1 genotypes were more frequent in the patients with cirrhosis (n=39, 87%) than in the control subjects (n=10; 18%) (odds ratio [OR] 34.04; 95% confidence interval [CI] 10.70 to 108.31, P<0.001). Among these patients with cirrhosis, 16 were heterozygous and 23 were homozygous, whereas only one person in the control group was homozygous. The GSTM1 null genotype was also more prevalent in cirrhotic patients than in healthy control subjects (OR 6.83, 95% CI 2.53 to 18.42, P<0.001). The rate of GSTT1 deletion did not show a significant difference between the two groups (OR 2.35, 95% CI 0.76 to 7.28, P=0.111). To our knowledge, this is the first evidence that GSTP1 and GSTM1 polymorphisms may be related to the development of cirrhosis by unknown mechanisms. The significant association of cryptogenic cirrhosis with Val/Val GSTP1 genotype encoding a low detoxification activity protein implicates this polymorphism as a risk factor for the occurrence of the disease.
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PMID:GSTP1, GSTM1, and GSTT1 genetic polymorphisms in patients with cryptogenic liver cirrhosis. 1512 Mar 66

Chronic hepatitis B virus (HBV) infection can cause severe liver disease, including cirrhosis and hepatocellular carcinoma. Lamivudine is a relatively recent alternative to alpha interferon for the treatment of HBV infection, but unfortunately, resistance to lamivudine commonly develops during monotherapy. Lamivudine-resistant HBV mutants display specific mutations in the YMDD (tyrosine, methionine, aspartate, aspartate) motif of the viral polymerase (reverse transcriptase [rt]), which is the catalytic site of the enzyme, i.e., methionine 204 to isoleucine (rtM204I) or valine (rtM204V). The latter mutation is often accompanied by a compensatory leucine-to-methionine change at codon 180 (rtL180M). In the present study, a novel sequencing method, pyrosequencing, was applied to the detection of lamivudine resistance mutations and was compared with direct Sanger sequencing. The new pyrosequencing method had advantages in terms of throughput. Experiments with mixtures of wild-type and resistant viruses indicated that pyrosequencing can detect minor sequence variants in heterogeneous virus populations. The new pyrosequencing method was evaluated with a small number of patient samples, and the results showed that the method could be a useful tool for the detection of lamivudine resistance in the clinical setting.
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PMID:Pyrosequencing for detection of lamivudine-resistant hepatitis B virus. 1547 42

It is well established that impaired glucose metabolism is a frequent complication in patients with hepatic cirrhosis. We previously showed that leucine, one of the branched-chain amino acids (BCAA), promotes glucose uptake under insulin-free conditions in isolated skeletal muscle from normal rats. The aim of the present study was to evaluate the effects of BCAA on glucose metabolism in a rat model of CCl(4)-induced cirrhosis (CCl(4) rats). Oral glucose tolerance tests were performed on BCAA-treated CCl(4) rats. In the CCl(4) rats, treatment with leucine or isoleucine, but not valine, improved glucose tolerance significantly, with the effect of isoleucine being greater than the effect of leucine. Glucose uptake experiments using isolated soleus muscle from the CCl(4) rats revealed that leucine and isoleucine, but not valine, promoted glucose uptake under insulin-free conditions. To clarify the mechanism of the blood glucose-lowering effects of BCAA, we collected soleus muscles from BCAA-treated CCl(4) rats with or without a glucose load. These samples were used to determine the subcellular location of glucose transporter proteins and glycogen synthase (GS) activity. Oral administration of leucine or isoleucine without a glucose load induced GLUT4 and GLUT1 translocation to the plasma membrane. GS activity was augmented only in leucine-treated rats and was completely inhibited by rapamycin, an inhibitor of mammalian target of rapamycin. In summary, we found that leucine and isoleucine improved glucose metabolism in CCl(4) rats by promoting glucose uptake in skeletal muscle. This effect occurred as a result of upregulation of GLUT4 and GLUT1 and also by mammalian target of rapamycin-dependent activation of GS in skeletal muscle. From these results, we consider that BCAA treatment may have beneficial effects on glucose metabolism in cirrhotic patients.
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PMID:Branched-chain amino acids improve glucose metabolism in rats with liver cirrhosis. 1559 Nov 58

Child-Pugh grading is an important determinant of treatment options, surgical interventions and prognosis in chronic liver disease. Sixty-four liver cirrhosis patients (49 men, 15 women) seen at Ile-Ife, Nigeria were graded according to the Child-Pugh parameters. Only one (1.6%) was in Class A, while 21 (32.8%) and 42 (65.6%) were in Classes B and C, respectively. Thirty-four either had coagulopathy or were already in encephalopathy at the time of presentation. Hepatitis B virus-associated disease was present in 64% of the patients. Most Nigerian cirrhosis patients present with very advanced disease; they are thus poor-risk candidates for diagnostic procedures and surgery. Efforts should be intensified at making the diagnosis at a much earlier stage and universal immunization with the hepatitis B vaccine should be commenced to reduce the incidence of HBV-related chronic liver disease in Nigeria.
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PMID:Liver cirrhosis: Child-Pugh grading of cases seen in Nigeria. 1610 47

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


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