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)

Patients with alpha1-antitrypsin (alpha1-AT) deficiency are at risk of developing early-onset panlobular basal emphysema, which has been attributed to uncontrolled proteolytic activity within the lung. Severe genetic deficiency of alpha1-AT is most commonly due to the Z mutation (342Glu--> Lys), which results in a block in alpha1-AT processing within the endoplasmic reticulum of hepatocytes. The retained alpha1-AT forms inclusions, which are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. Our recent studies have shown that the accumulation of alpha1-AT is due to the Z mutation perturbing the structure of alpha1-AT to allow polymer formation, with a unique linkage between the reactive center loop of one alpha1-AT molecule and the A beta-pleated sheet of a second. The detection of loop-sheet polymers and other conformations of alpha1-AT in the lungs of patients with emphysema has been technically difficult. We show here that transverse urea-gradient-gel (TUG) electrophoresis and Western blot analysis may be used to characterize conformations of alpha1-AT in dilute samples of bronchoalveolar lavage fluid (BALF). This technique was used to demonstrate loop-sheet polymers in the lungs of patients with Z alpha1-AT-deficiency-related emphysema. Polymers were the predominant conformational form of alpha1-AT in BALF from the lungs of two of five Z homozygotes with emphysema, but were not detectable in any of 13 MM, MS, or MZ alpha1-AT controls. Because alpha1-AT loop-sheet polymers are inactive as proteinase inhibitors, this novel conformational transition will further reduce the levels of functional proteinase inhibitor in the lungs of the Z alpha1-AT homozygote, and so exacerbate tissue damage.
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PMID:Lung polymers in Z alpha1-antitrypsin deficiency-related emphysema. 956 37

The effects of carbon tetrachloride (CCl4) on the liver in spontaneously hypertensive rat (SHR) and Wistar-Kyoto rat (WKY) were investigated ultrastructurally in this study. Repetition of CCl4 treatment twice a week for four weeks, revealed liver cirrhosis in SHR, whereas, only bridging fibrosis was observed in the WKY, histologically, by reticulin silver impregnation. Scanning electron microscopy revealed that the liver surface of SHR was irregularly nodulated, while it was relatively smooth in case of the WKY. Transmission electron microscopy revealed that the mitochondria cristae were peripherally located in both strains. Vesicular change of the rough endoplasmic reticulum was observed to be more severe in SHR than in WKY. Further, local hypertrophy of the smooth endoplasmic reticulum and large lipid droplets were more easily observed in WKY than in SHR. The present results hence indicate that chronic chemical CCl4 intoxication induces severe ultrastructural organelle damage in hypertensive rats, leading to liver cirrhosis. On the other hand, CCl4 induced fatty liver and a relatively mild fibrosis were observed in normotensive rats. These findings suggest that the liver ultrastructural organelles are more susceptible to CCl4 in SHR than in WKY.
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PMID:Ultrastructural changes in liver damage induced by carbon tetrachloride in spontaneously hypertensive rats and Wistar-Kyoto rats. 968 7

Genetic haemochromatosis (GH) is one of the most common hereditary diseases, with a prevalence of 1-5/1000 in the Western world. In 90 per cent of cases a mutation is found in an MHC-class-like gene designated HFE, involving a substitution at position 282 of the HFE protein and resulting in defective binding of beta(2)-microglobulin. Animals with beta(2)-microglobulin deficiency develop iron overload, indicating this protein to be involved in the regulation of iron metabolism. Hepatic iron overload results in increased production of oxygen free radicals and peroxidation of membrane lipids, thus causing damage to lysosomes, mitochondria and the endoplasmic reticulum. These cellular events may progress to cell death, fibrogenesis, and the development of liver cirrhosis which is associated with a 200-fold increase in risk of hepatocellular carcinoma. In addition to the risk of diabetes, arthralgia, cardiac arrhythmia, pituitary insufficiency and hypogonadism, iron excess is also associated with aggravation of the cytotoxic effects exerted on hepatocytes by other agents such as alcohol or hepatotrophic viruses. The treatment of iron overload in GH consists of weekly venesection until the serum ferritin level is normalized, followed by maintenance therapy. Survival rates are normal if the disease is detected and treated before complications have developed.
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PMID:[Defective iron metabolism in genetic hemochromatosis. The mechanisms remain unknown in spite of genetic advances]. 972 62

Lesions produced by Fasciola hepatica in the liver, gall-bladder and hepatic lymph nodes (HLNs) of four groups of five goats are described; in addition, the distribution of CD3+ T lymphocytes and IgG-lambda light chain-bearing cells was analysed in the hepatic lesions and HLNs. One group of goats received a single oral dose of metacercariae, but the other four groups received four or five doses at different intervals over a period of 11 weeks. Animals that survived were killed 53-55 weeks after the first infective dose. Goats were more susceptible to multiple doses than to a single dose, even when the total number of metacercariae was the same. This greater susceptibility was manifested by the occurrence of deaths and the severity of hepatic lesions. CD3+ lymphocytes were sparse in the infiltrate surrounding the acute migratory tracts, suggesting inhibition of the local cell-mediated immune response. Goats with numerous hepatic calcareous granulomas showed the most severe hepatic damage, including marked cirrhosis, with a striking infiltrate of CD3+ T lymphocytes and lambda IgG- plasma cells, replacing extensive areas of hepatic parenchyma, in which hypertrophy of the smooth endoplasmic reticulum of hepatocytes was evident. These findings were observed mainly in the goats given more than one infective dose.
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PMID:Pathological and immunohistochemical study of the liver and hepatic lymph nodes in goats infected with one or more doses of Fasciola hepatica. 1008 93

Hepatitis B virus is a major cause of human liver disease. In the case of chronic infection the virus can lead to liver cancer and cirrhosis. The virion consists of an outer envelope containing lipids of the endoplasmic reticulum and virally-encoded surface proteins. This lipoprotein shell encloses the nucleocapsid or core antigen (HBcAg), which contains the viral genome. The capsid consists of dimers of a 183-residue protein, which can be divided into an assembly (residues 1-149) and a protamin-like domain (residues 150-183), responsible for polymerization into particles and RNA packaging, respectively. Upon expression of the core gene in bacteria the products are assembled into capsids resembling those of wild type particles. A purification protocol was developed for unpolymerised (dimeric) and polymerized HBcAg by fusion of six histidine residues to a C-terminal deletion mutant of the core protein allowing the isolation of the respective antigens after denaturing Ni2+-chelate affinity chromatography and renaturing dialysis. The possible incorporation of E. coli proteins during the assembly process and the inclusion of nucleic acids can be avoided. The method might be an attractive alternative to common purification protocols of hybrid virus-like particles (VLPs) for vaccine use.
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PMID:Purification of E. coli-expressed HIS-tagged hepatitis B core antigen by Ni2+ -chelate affinity chromatography. 1009 42

The mutation in the Z deficiency variant of alpha1-antitrypsin perturbs the structure of the protein to allow a unique intermolecular linkage. These loop-sheet polymers are retained within the endoplasmic reticulum of hepatocytes to form inclusions that are associated with neonatal hepatitis, juvenile cirrhosis, and hepatocellular carcinoma. The process of polymer formation has been investigated here by intrinsic tryptophan fluorescence, fluorescence polarization, circular dichroic spectra and extrinsic fluorescence with 8-anilino-1-naphthalenesulfonic acid and tetramethylrhodamine-5-iodoacetamide. These biophysical techniques have demonstrated that alpha1-antitrypsin polymerization is a two-stage process and have allowed the calculation of rates for both of these steps. The initial fast phase is unimolecular and likely to represent temperature-induced protein unfolding, while the slow phase is bimolecular and associated with loop-sheet interaction and polymer formation. The naturally occurring Z, S, and I variants and recombinant site-directed reactive loop and shutter domain mutants of alpha1-antitrypsin were used to demonstrate the close association between protein stability and rate of alpha1-antitrypsin polymerization. Taken together, these data allow us to propose a kinetic mechanism for alpha1-antitrypsin polymer formation that involves the generation of an unstable intermediate, which can form polymers or generate latent protein.
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PMID:A kinetic mechanism for the polymerization of alpha1-antitrypsin. 1009 40

We examined the expression of smooth muscle cytoskeleton in spindle-shaped cells in the capsule of hepatocellular carcinoma (HCC) and the septa of liver cirrhosis (LC). Serial sections of livers resected from 11 patients were stained with monoclonal antibodies against vimentin, desmin, smooth muscle actin (1A4, HHF35, CGA7) and smooth muscle myosin heavy chain isoforms (SM1, SM2). Capsular spindle-shaped cells exhibited a cytoskeletal feature indicative of intermediately differentiated smooth muscle cells. Computer-assisted morphometry revealed that the proportions of 1A4-, HHF35-, CGA7- and SM1- positive areas to vimentin-positive area were 88.0+/-11.0%, 50.8+/-17.4%, 25.3+/-16.4% and 19.4+/-12.4% (n=11) in main tumours and 86.6+/-9.4%, 50.9+/-18.7%, 21.1+/-12.3% and 17.6+/-9.7% (n=12) in daughter tumours, indicating that spindle-shaped cells are heterogeneous in cytoskeletal expression. Septal spindle-shaped cells in LC lacked the cytoskeletal proteins specific to differentiated smooth muscle cells (CGA7, SM1, SM2 and desmin). Electron microscopically, capsular spindle-shaped cells contained more microfilaments and less rough endoplasmic reticulum than do septal cells. Intermediately differentiated smooth muscle cells are induced in the capsule of HCC but not in the septa of LC, suggesting a role for stromal interaction by tumour cells in the induction of smooth muscle cells.
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PMID:Induction of smooth muscle cells in the fibrous capsule of human hepatocellular carcinoma but not in the septa of hepatic cirrhosis. 1038 24

Iron, either in the form of heme or non-heme compounds, is essential to life, but it can also pose serious health risks. The liver is a principal target for iron toxicity because it is chiefly responsible for taking up and storing excessive amounts of iron. The major hepatic toxicities of iron overload include damage to multiple cell types (hepatocytes, Kupffer cells, hepatic stellate cells) and to multiple subcellular organelles (mitochondria, lysosomes, and smooth endoplasmic reticulum). Heavy iron overload, as occurs in primary (hereditary) or secondary forms of hemochromatosis, may cause cirrhosis, liver failure, and hepatocellular carcinoma. In addition, iron has been shown to be a contributory factor in the development or progression of alcoholic liver disease, nonalcoholic liver steatohepatitis, chronic viral hepatitis, prophyria cutanea tarda, and, perhaps, in alpha 1-antitrypsin deficiency and end-stage liver disease, regardless of cause.
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PMID:Iron-induced liver injury. 1123 98

A case of lipid-rich clear-cell hepatocellular carcinoma arising in non-alcoholic steatohepatitis is described in a patient with diabetes mellitus. The patient was a 67 year-old Japanese female with a history of tuberculosis, appendicitis, ischaemic heart disease, and non-insulin-dependent diabetes mellitus. The patient denied alcohol consumption. A liver mass was diagnosed as hepatocellular carcinoma of clear-cell type with early cirrhosis of the peri-tumoral liver tissue. Tumour cells had clear cytoplasm containing lipid droplets, and Mallory bodies. Surrounding non-tumoral liver tissue also showed lipid, and fibrosis in peri-portal areas with moderate bridging fibrosis. The features were consistent with clear-cell hepatocellular carcinoma arising in the fibrosis of non-alcoholic steatohepatitis. By electron microscopy, tumour cells had lipid droplets, glycogen, swollen mitochondria, rough endoplasmic reticulum, Mallory bodies, small bile canaliculi, desmosomes and gap junctions. Surrounding non-tumoral hepatocytes had a largely normal ultrastructure with prominent glycogen and lipid droplets. Clear-cell hepatocellular carcinoma within non-alcoholic steatohepatitis associated with diabetes mellitus is an extremely rare condition, and this report provides a detailed histopathological description with both immunohistochemical and ultrastructural data.
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PMID:Lipid-rich clear-cell hepatocellular carcinoma arising in non-alcoholic steatohepatitis in a patient with diabetes mellitus. 1168 2

Hepatitis C virus (HCV) is the major causative pathogen associated with liver cirrhosis and hepatocellular carcinoma. The virus has a positive-sense RNA genome encoding a single polyprotein with the virion components located in the N-terminal portion. During biosynthesis of the polyprotein, an internal signal sequence between the core protein and the envelope protein E1 targets the nascent polypeptide to the endoplasmic reticulum (ER) membrane for translocation of E1 into the ER. Following membrane insertion, the signal sequence is cleaved from E1 by signal peptidase. Here we provide evidence that after cleavage by signal peptidase, the signal peptide is further processed by the intramembrane-cleaving protease SPP that promotes the release of core protein from the ER membrane. Core protein is then free for subsequent trafficking to lipid droplets. This study represents an example of a potential role for intramembrane proteolysis in the maturation of a viral protein.
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PMID:Intramembrane proteolysis promotes trafficking of hepatitis C virus core protein to lipid droplets. 1214 99


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