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)

Alpha-1-antitrypsin deficiency results from point mutations that distort the structure of the protein to allow a unique protein-protein interaction that we have termed loopsheet polymerisation. Polymers of Z alpha 1-antitrypsin accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha 1-antitrypsin homozygote to emphysema. This process also occurs in other members of the serine proteinase inhibitor (serpin) superfamily, antithrombin, C1-inhibitor and alpha 1-antichymotrypsin, in association with thrombosis, angioedema and chronic obstructive pulmonary disease, respectively, and we have recently shown that it underlies a novel inclusion body dementia. The interaction provides a useful paradigm for other 'conformational diseases' such as Huntington's disease, Creutzfeldt-Jakob disease and the amyloidoses.
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PMID:Alpha-1-antitrypsin deficiency, the serpinopathies and conformational disease. 1090 27

Alpha1-antitrypsin deficiency results from point mutations that distort the structure of the protein to allow a unique protein-protein interaction that we have termed loop-sheet polymerization. Polymers of Z alpha1-antitrypsin accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha1-antitrypsin homozygote to emphysema. This polymerization process also occurs in variants of other members of the serine proteinase inhibitor (serpin) superfamily, antithrombin, C1-inhibitor and alpha1-antichymotrypsin in association with thrombosis, angiooedema and chronic obstructive pulmonary disease respectively, and we have recently shown that it underlies a novel inclusion body dementia. Understanding this mechanism of polymerization allows rational drug design to block the protein-protein linkage and so ameliorate the associated disease.
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PMID:Loop-sheet polymerization: the mechanism of alpha1-antitrypsin deficiency. 1095 47

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

Alpha(1)-antitrypsin functions as a "mousetrap" to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu(342)-->Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and beta-sheet A of another. These loop-sheet polymers accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha(1)-antitrypsin homozygote to emphysema. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and alpha(1)-antichymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.
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PMID:Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia. 1202 31

Polymerization of members of the serpin superfamily underlies diseases as diverse as cirrhosis, angioedema, thrombosis and dementia. The Drosophila serpin Necrotic controls the innate immune response and is homologous to human alpha(1)-antitrypsin. We show that necrotic mutations that are identical to the Z-deficiency variant of alpha(1)-antitrypsin form urea-stable polymers in vivo. These necrotic mutations are temperature sensitive, which is in keeping with the temperature-dependent polymerization of serpins in vitro and the role of childhood fevers in exacerbating liver disease in Z alpha-antitrypsin deficiency. In addition, we identify two nec mutations homologous to an antithrombin point mutation that is responsible for neonatal thrombosis. Transgenic flies carrying an S>F amino-acid substitution equivalent to that found in Siiyama-variant antitrypsin (nec(S>F.UAS)) fail to complement nec-null mutations and demonstrate a dominant temperature-dependent inactivation of the wild-type nec allele. Taken together, these data establish Drosophila as a powerful system to study serpin polymerization in vivo.
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PMID:Drosophila necrotic mutations mirror disease-associated variants of human serpins. 1258 61

The mechanisms leading to the hemostatic changes of acute liver injury are poorly understood. To study these further we have assessed coagulation and immune changes in patients with acute paracetamol overdose and compared the results to patients with chronic cirrhosis and normal healthy controls. The results demonstrate that in paracetamol overdose coagulation factors (F)II, V, VII and X were reduced to a similar degree and were significantly lower than FIX and FXI (mean levels 0.28, 0.16, 0.13, 0.19, 0.51 and 0.72 IU mL(-1), respectively). In cirrhosis, by contrast, FII, FV, FVII, FIX and FX were equally reduced whilst FXI was lower than the other factors (mean levels 0.64, 0.69, 0.62, 0.60, 0.66 and 0.40 IU mL-1, respectively). FVIII was raised in paracetamol overdose patients but normal in those with cirrhosis (mean levels 1.95 and 1.01 IU mL(-1), respectively). Interleukin-6 and tumor necrosis factor-alpha levels were raised in both patient groups, but higher levels were found in paracetamol overdose, compared to cirrhosis. Thrombin-antithrombin and soluble tissue factor levels were higher in those with acute liver injury but normal in cirrhosis. Antithrombin levels were reduced in both acute liver injury and cirrhosis. From these data we put forward a novel mechanism for the coagulation changes in acute paracetamol induced liver injury. We propose that immune activation leads to tissue factor-initiated consumption of FII, FV, FVII and FX, but that levels of FIX and FXI are better preserved because antithrombin inhibits the thrombin induced positive feedback loop that activates these latter factors.
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PMID:Effects of acute liver injury on blood coagulation. 1287 12

The precise mechanisms leading to the coagulopathy of acute liver injury are unclear. To study this further, coagulation and immune changes have been compared in patients with acute liver injury secondary to paracetamol overdose, with chronic cirrhosis, and normal healthy controls. In acute liver injury, coagulation factors II, V, VII and X were reduced to a similar degree, and were significantly lower than factors IX and XI. In cirrhosis, by contrast, these coagulation factors were reduced to similar levels. Factor VIII increased in acute liver injury, but was normal in cirrhosis. Interleukin-6 and tumour necrosis factor-alpha levels increased in both patient groups, but were higher in paracetamol overdose. Thrombin-antithrombin and soluble tissue factor levels increased in those with acute liver injury, but were normal in patients with cirrhosis. Functional antithrombin was reduced in both acute liver injury and cirrhosis. It is hypothesized that in acute paracetamol-induced liver injury, immune activation leads to tissue factor-initiated consumption of factors II, V, VII and X, but that levels of factors IX and XI are better preserved because of inhibition of the thrombin-induced amplification phase of coagulation. These findings have implications for appropriate coagulation factor support for patients with acute liver injury.
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PMID:New insights into haemostasis in liver failure. 1456 36

The serpins differ from the many other families of serine protease inhibitors in that they undergo a profound change in topology in order to entrap their target protease in an irreversible complex. The solving of the structure of this complex has now provided a video depiction of the changes involved. Cleavage of the exposed reactive centre of the serpin triggers an opening of the five-stranded A-sheet of the molecule, with insertion of the cleaved reactive loop as an additional strand in the centre of the sheet. The drastic displacement of the acyl-linked protease grossly disrupts its active site and gives an overall loss of 40% of ordered structure. This ability to provide effectively irreversible inhibition explains the selection of the serpins to control the proteolytic cascades of higher organisms. The conformational mechanism provides another advantage in its potential to modulate activity. Sequential crystallographic structures now provide clear depictions of the way antithrombin is activated on binding to the heparans of the microcirculation, and how evolution has utilized this mobile mechanism for subtle variations in activity. The complexity of these modulatory mechanisms is exemplified by heparin cofactor II, where the change in fold is seen to trigger multiple allosteric effects. The downside of the mobile mechanism of the serpins is their vulnerability to aberrant intermolecular beta-linkages, resulting in various disorders from cirrhosis to thrombosis. These provide a well defined structural prototype for the new entity of the conformational diseases, including the common dementias, as confirmed by the recent identification of the familial neuroserpin dementias.
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PMID:How serpins change their fold for better and for worse. 1458 91

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

Hepatocellular carcinoma (HCC) patients have an increased risk for venous thromboembolism, mainly portal venous thrombosis (PVT). The aim of this study was to assess the role of acquired and hereditary thrombotic risk factors in HCC patients. Thirty-one patients with HCC, 30 patients with cirrhosis but without HCC or PVT, and 48 matched healthy controls were studied. Mean levels of plasma protein C, protein S, antithrombin, and serum lipoprotein (a) were significantly lower in patients with HCC and in the cirrhotic group compared to the healthy controls. Mean serum homocysteine levels were significantly higher in patients with HCC compared to cirrhotics and healthy controls. The prevalence of activated protein C resistance, factor V Leiden mutation, prothrombin gene mutation G20210GA, and C677T methylenetetrahydrofolate reductase polymorphism was not significantly different among the three groups. In conclusion, thrombophilic defects are common in HCC patients and they might contribute to the observed thrombotic complications in this malignancy.
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PMID:Hypercoagulable states in patients with hepatocellular carcinoma. 1525 9


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