Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019158 (hepatitis)
 30,205 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The respective roles of intravascular coagulation (DIC) and fibrinolysis were assessed in severe chronic liver disease by measuring thrombin-antithrombin (TAT) complexes, tissue-type plasminogen activator antigen (tPA Ag) and fibrinogen and fibrin degradation products (FgDP and FbDP respectively) in 66 patients with liver disease caused by cirrhosis (n = 34) or chronic hepatitis (n = 32) as compared to findings in a control group (n = 30). There was a significant increase of TAT complexes (P less than 0.01), tPA Ag (P less than 0.002), FDP and FbDP (P less than 0.001) in patients as compared to controls. FbDP increase was more evident in patients with cirrhosis than in those with hepatitis (P less than 0.01). Significant correlations between these parameters with some liver function tests were also demonstrated. Thus, in patients with severe liver disease, an increased thrombin activity, as demonstrated by high TAT levels; followed by hyperfibrinolysis suggest that a low grade DIC may occur.
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PMID:Thrombin activation and increased fibrinolysis in patients with chronic liver disease. 190 1

Antithrombin III is of potential value for replacement therapy in patients with acquired or congenital deficiencies. Pasteurization of the purified inhibitor for 10 h at 60 degrees C can reduce the risk of transfusion hepatitis. Addition of appropriate stabilizers can largely prevent the loss of antithrombin activity which otherwise occurs during pasteurization. Studies of the mechanism of denaturation and stabilization have been facilitated by the use of 8-anilino-1-naphthalene sulfonate which binds weakly to the inhibitor and whose fluorescence undergoes a sigmoidal response to increasing temperature. The extent of the increase in 8-anilino-1-naphthalene sulfonate fluorescence correlates roughly with the loss of antithrombin activity and with the extent of protein aggregation as determined by high pressure liquid chromatography. The midpoint, Td, of the thermal denaturation curve increases by 13 degrees C and 19 degrees C in the presence of 0.5 M and 1.0 M sodium citrate, respectively. Phosphate, sulfate, and EDTA are also strong stabilizers while the chaotropic anions, iodide and thiocyanate are potent destabilizers. Heparin at 10 mg/ml increases Td by 7 degrees C, presumably through a direct binding mechanism; chondroitin sulfate and hyaluronic acid have no effect. Samples pasteurized for 10 h at 60 degrees C in the presence of 0.5 M and 1.0 M citrate retain essentially full activity but exhibit evidence of minor alterations in their interaction with heparin.
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PMID:Thermal denaturation of antithrombin III. Stabilization by heparin and lyotropic anions. 729 49

Conformational diseases such as amyloidosis, Alzheimer's disease, prion diseases, and the serpinopathies are all caused by structural rearrangements within a protein that transform it into a pathological species. These diseases are typified by the Z variant of alpha(1)-antitrypsin (E342K), which causes the retention of protein within hepatocytes as inclusion bodies that are associated with neonatal hepatitis and cirrhosis. The inclusion bodies result from the Z mutation perturbing the conformation of the protein, which facilitates a sequential interaction between the reactive center loop of one molecule and beta-sheet A of a second. Therapies to prevent liver disease must block this reactive loop-beta-sheet polymerization without interfering with other proteins of similar tertiary structure. We have used reactive loop peptides to explore the differences between the pathogenic Z and normal M alpha(1)-antitrypsin. The results show that the reactive loop is likely to be partially inserted into beta-sheet A in Z alpha(1)-antitrypsin. This conformational difference from M alpha(1)-antitrypsin was exploited with a 6-mer reactive loop peptide (FLEAIG) that selectively and stably bound Z alpha(1)-antitrypsin. The importance of this finding is that the peptide prevented the polymerization of Z alpha(1)-antitrypsin and did not significantly anneal to other proteins (such as antithrombin, alpha(1)-antichymotrypsin, and plasminogen activator inhibitor-1) with a similar tertiary structure. These findings provide a lead compound for the development of small molecule inhibitors that can be used to treat patients with Z alpha(1)-antitrypsin deficiency. Furthermore they demonstrate how a conformational disease process can be selectively inhibited with a small peptide.
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PMID:6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis. 1177 44

Fresh frozen plasma (FFP) contains higher levels of intact coagulation factors and coagulation and fibrinolysis inhibitors than solvent/detergent-treated plasma (SD plasma), and also greater residual cell contamination. SD plasma is a particle-free plasma of uniform quality. SD treatment, however, has the specific result of reducing the activities of some inhibitors. Both plasma types carry a minimal residual risk of transmitting human immunodeficiency virus (HIV)-1/2, hepatitis virus B (HBV), and hepatitis virus C (HCV), but SDP is, in addition, also safe with respect to other lipid-enveloped viruses and perhaps with respect to hepatitis virus A (HAV), also due to its antibody (Ab) content. Future revisions of therapeutic plasma safety and quality standards should consider the following points:For FFP:reduce residual cell count in all FFP units to values below 5 x 10(6) leukocytes/l;screen donors for Parvovirus B19 genome and antibodies in order to establish a sufficiently large collection of genome-negative and antibody-positive donors whose FFP can be used for selected patients;For SDP:introduce pool testing for Parvovirus B19 genome; fix an upper limit for genome and a lower limit for antibody content;in addition to the standard quality control methods for therapeutic plasma, focus on assays to test for functionally intact proteinase inhibitors such as alpha(2)antiplasmin (alpha(2)AP) and alpha(1)proteinase inhibitor (alpha(1)PI) that are important for plasma indications. Commercially available kits may not be sufficient to show changes in inhibition kinetics. For both types:introduce an activation marker such as thrombin-antithrombin complex (TAT) as a random test to monitor activation processes during withdrawal, separation, manufacturing, and storage;abolish inappropriate parameters like Antithrombin III (AT III) and coagulation factor XI that are not relevant for changes in plasma quality;finally, support every effort towards establishing an efficient documentation and reporting system on efficacy and side effects of plasma transfusions. Effective reporting alone might help to reveal deficiencies of specific plasma quality and to overcome them through modifications to manufacturing processes and testing, or by defining its indications more precisely.
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PMID:Quality of therapeutic plasma-requirements for marketing authorization. 1237 93

Blood collected by 11 Red Cross Regional Blood Centers were screened by the method of agar gel diffusion (AGD) for the presence of hepatitis-B antibody. Of the 185,134 units tested, 114 were found to be positive for HBAb by the Regional Centers and were forwarded to National Special Projects Laboratory for confirmation. Only five out of 114 samples revealed lines of identity with a control anti-HBAg when reacted with a pool of plasma positive for hepatitis-B antigen that was different from that which was provided to the Centers. Apparently, the precipitation reactions observed by the Centers were largely due to the antithrombin antibodies in the donors' sera reacting with the residual thrombin used by the manufacturer to convert HBAg positive plasma to serum. We conclude that the incidence of hepatitis-B antibody as measured by agar gel diffusion in the Red Cross Blood donor population was extremely low.
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PMID:American National Red Cross experience with hepatitis-B antibody (HBAb or anti-HBAg) testing. 1273 88

Alpha-1-antitrypsin (alpha(1)-antitrypsin) is the archetypal member of the serine proteinase inhibitor or serpin superfamily. The most common severe deficiency variant is the Z allele, which results in the accumulation of mutant protein within hepatocytes. This 'protein overload' causes neonatal hepatitis, cirrhosis and hepatocellular carcinoma. The lack of circulating plasma alpha(1)-antitrypsin results in early-onset panlobular emphysema. The mechanism underlying the deficiency of Z alpha(1)-antitrypsin is due to an aberrant conformational transition within the protein and the formation of chains of polymers that tangle within the secretory pathway of hepatocytes. This mechanism also underlies the plasma deficiency of other members of the serpin superfamily to cause a class of diseases called the serpinopathies. Specifically mutant alleles of antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin have been reported that favour the spontaneous formation of polymers and the retention of protein within hepatocytes. The consequent lack of plasma antithrombin, C1-inhibitor and alpha(1)-antichymotrypsin results in thrombosis, angio-oedema and emphysema, respectively. Moreover, the polymerisation of mutants of neuroserpin results in the retention of polymers within neurones to cause the inclusion body dementia, familial encephalopathy with neuroserpin inclusion bodies or FENIB. We review here the genetic and molecular basis and clinical features of alpha(1)-antitrypsin deficiency, and show how this provides a platform to understand the other serpinopathies.
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PMID:Practical genetics: alpha-1-antitrypsin deficiency and the serpinopathies. 1469 55

Separation of concentrated bile acids from hepatic parenchymal cells is a key function of the bile duct epithelial cells (BDECs) that form intrahepatic bile ducts. Using coimmunostaining, we found that tissue factor (TF), the principal activator of coagulation, colocalized with cytokeratin 19, a marker of BDECs in the adult mouse liver. BDEC injury induced by xenobiotics such as alpha-naphthylisothiocyanate (ANIT) causes cholestasis, inflammation, and hepatocellular injury. We tested the hypothesis that acute ANIT-induced cholestatic hepatitis is associated with TF-dependent activation of coagulation and determined the role of TF in ANIT hepatotoxicity. Treatment of mice with ANIT (60 mg/kg) caused multifocal hepatic necrosis and significantly increased serum biomarkers of cholestasis and hepatic parenchymal cell injury. ANIT treatment also significantly increased liver TF expression and activity. ANIT-induced activation of the coagulation cascade was shown by increased plasma thrombin-antithrombin levels and significant deposition of fibrin within the necrotic foci. ANIT-induced coagulation and liver injury were reduced in low-TF mice, which express 1% of normal TF levels. The results indicate that ANIT-induced liver injury is accompanied by TF-dependent activation of the coagulation cascade and that TF contributes to the progression of injury during acute cholestatic hepatitis.
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PMID:Tissue factor-dependent coagulation contributes to alpha-naphthylisothiocyanate-induced cholestatic liver injury in mice. 1917 21