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 analyze relating factors to early repairment of the surgical margin of the remnant liver we measured plasma fibronectin (FN), coagulation factor XIII (XIII), polymorphonuclear leukocyte elastase (PMNE), platelet counts (Plt), prothrombin time (PT%) before and at the first, third, 7th and 14th days after liver resection in 25 patients. Changes in these factors (1) were compared with their clinical status, such as liver cirrhosis, high fever, abscess formation, duration of drainage and use of microwave tissue coagulator (MTC) (2). The multivariate analysis about the factors influencing the duration of hospital stay (3) were carried out. (1) In the all cases FN, XIII (14th), PT%, Plt decreased and PMNE increased significantly versus pre-operative data. There were significant correlations between FN and XIII, FN and PMNE. (2) In the cirrhotic group FN, XIII, PT% and Plt were significantly lower than those of non cirrhotic group. In the abscess formation group PT% was significantly lower than the no abscess formation group. In the MTC group XIII, PT% and Plt were significantly lower than those of the no-MTC group. In conclusion, FN, XIII, Plt and PT% in the cirrhotic, high fever, abscess formation or longer drainage group were in lower levels compared with the each control group. (3) By the multivariate analyses, abscess formation, high fever and liver cirrhosis were the most influencing factors for the duration of hospital stay.
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PMID:[Analysis of factors relating to early repairment of the surgical margin following liver resection--factors relating to duration of hospital stay]. 187 92

Alpha-1-antitrypsin (AAT) is the predominant protease inhibitor in human sera. The major physiological role of this inhibitor is to protect elastin fibers in the alveolar structure of the lung from excessive degradation by neutrophil elastase. AAT is synthesized predominantly by hepatocytes, although the AAT gene is expressed to a small degree in the epithelial cells of various tissues. Recent studies have shown that the enhanced liver-specific expression of the AAT gene is controlled by the binding of hepatic nuclear proteins to specific DNA sequences upstream from the structural gene. A variety of mutations within the AAT gene have been identified that result in a partial deficiency or total absence of the inhibitor in sera. Inheritance of a particular combination of these alleles can result in a predisposition towards the development of destructive lung disease. Interestingly, the most common AAT deficiency variant, designated PiZ, causes the mutant protein to accumulate as an insoluble aggregate within the lumen of the hepatic rough endoplasmic reticulum, which is an etiological agent for the development of liver disease. Overall, investigation into the genetic control of AAT has led to an increased understanding of the factors that control hepatic gene expression, as well as mechanisms involved in the pathophysiology of emphysema and liver cirrhosis.
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PMID:Genetic control of human alpha-1-antitrypsin. 269 88

Alpha-1-protease inhibitor (A1PI) exists in over 30 biochemical variants (the Pi system), inherited as autosomal codominant alleles. Homozygotes of Pi type Z have only 10 to 20 percent of the normal serum A1PI concentration and have a high risk of developing pulmonary emphysema. A1PI is an inactivator of polymorph lysosomal elastase, the unopposed action of which may damage the lung. Cigarette smoking is an important additional risk factor. Neonatal hepatitis occurs in 10 to 20 percent of Pi type Z persons, and cirrhosis develops in a number of them in later childhood or in adult life. In heterozygotes of Pi type MZ, pulmonary or hepatic disease may also develop, though they are at lesser risk than type Z homozygotes. Specific A1PI replacement therapy derived from human plasma is now available and has been administered to Pi type Z patients by weekly intravenous infusion without adverse effects. A controlled clinical trial would be desirable, though this would be attended by organizational and economic problems.
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PMID:Natural history of alpha-1-protease inhibitor deficiency. 328 86

alpha 1-Antitrypsin (AAT) deficiency is associated with predisposition to developing liver cirrhosis in early childhood, and chronic degenerative lung disease in early adult life. The probable molecular basis for the disease associations is known. One of the common variants, Z, has the propensity to form polymers, a phenomenon which is concentration- and temperature-dependent. This results in accumulation of the protein in hepatocytes, the predominant tissue source of AAT, and leads to cell damage. AAT deficiency results in loss of protection in the lung against neutrophil elastase (NE) the major target for AAT. NE is capable of destroying the architecture of the lung, leading to pulmonary emphysema. The disease process is exacerbated by cigarette smoke, which is capable of oxidizing a critical methionine residue at the active site, rendering AAT an inefficient inhibitor of NE. The combination of deficiency and cigarette smoking are critical to the development of pulmonary emphysema. We have identified a mutation in an enhancer sequence which, in all probability, predisposes to disease by a novel mechanism related to diminished expression of AAT during inflammation. Our understanding of the mechanisms of disease should lead to improved therapeutic interventions.
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PMID:Molecular pathology of alpha 1-antitrypsin deficiency and its significance to clinical medicine. 782 May 38

alpha 1-Antitrypsin is a circulating serine proteinase inhibitor that protects the lungs against proteolysis by the enzyme neutrophil elastase. Most northern Europeans have only the normal M form, but some 4% are heterozygotes for the Z deficiency mutant. This mutant is characterized by the substitution of a positively charged lysine residue for a negatively charged glutamic acid at position 342 and results in normal gene translation but reduced protein secretion into the plasma. The plasma levels of antitrypsin in homozygotes are only 15% of normal, the other 85% being retained in the endoplasmic reticulum of the hepatocyte. This review describes the effect of the Z mutation on the structure and function of antitrypsin and illustrates the importance of understanding protein structure in solving the mechanism of Z antitrypsin retention within the liver. We demonstrate that antitrypsin accumulation in the liver results from a unique interaction between antitrypsin molecules. The Z mutation perturbs the gap between the third and fifth strands of the A sheet, allowing the reactive center loop of one molecule to insert into the A sheet of a second. This loop-sheet polymerization results in the formation of chains of protein which form insoluble inclusions in the endoplasmic reticulum, resulting in hepatocellular damage and cirrhosis. In addition, the Z mutation results in a distortion of the circular dichroic spectrum, a rearrangement of the reactive center loop with respect to the A sheet, and a reduction in association rate constant with the cognate proteinase neutrophil elastase.
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PMID:A protein structural approach to the solution of biological problems: alpha 1-antitrypsin as a recent example. 821 81

1. alpha 1-antitrypsin is an antiprotease that inhibits the neutrophil elastase enzyme, and belongs to a family of structurally related serine proteinase inhibitors (serpins). Its methionine358 residue determines the specificity for elastase. 2. The normal M-type alpha 1-antitrypsin is mainly synthesized in the liver parenchymal cells and transported to the plasma. Abnormal Z-mutant alpha 1-antitrypsin is retained in the endoplasmic reticulum, which leads to its intracellular accumulation and to markedly decreased plasma levels. 3. In normal conditions, alpha 1-antitrypsin protects the lungs from destruction by the proteolytic neutrophil elastase. A protease/antiprotease imbalance in the lung is responsible for the development of emphysema in severe alpha 1-antitrypsin deficiency and in cigarette smokers, and accounts for the marked acceleration of the lung disease in smoking alpha 1-antitrypsin deficient patients. Smoking has to be avoided in alpha 1-antitrypsin deficient patients. Replacement therapy with plasma-derived alpha 1-antitrypsin seems indicated in alpha 1-antitrypsin deficient patients with emphysema. 4. Intracellular accumulation of abnormal Z-alpha 1-antitrypsin molecules in liver parenchymal cells may lead to liver disease, ranging from neonatal cholestasis to adulthood cirrhosis and hepatocellular carcinoma. End-stage liver disease can be treated by liver transplantation, which is followed by a phenotypic conversion. 5. Diagnosis of alpha 1-antitrypsin deficiency related disease relies on the presence of a low serum concentration of alpha 1-antitrypsin, and of periodic-acid Schiff positive globules in the liver parenchymal cells. Isoelectric focusing of the serum identifies the protease inhibitor phenotype. The protease inhibitor phenotype is determined by the independent expression of the two parental alpha 1-antitrypsin alleles. It is determinant of the serum level and of the risk for development of lung or liver disease.
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PMID:Alpha 1-antitrypsin deficiency: an overview. 839 99

Alpha-1-antitrypsin is a glycoprotein which inactivates proteolytic enzymes, especially neutrophil elastase. Infants deficient in this enzyme commonly develop neonatal hepatitis. In adults, the deficiency typically results in emphysema. Only rarely will an adult manifest liver disease. We present a case of adult liver cirrhosis due to Alpha-1-antitrypsin deficiency in a 63-year-old man. Manifestations of alpha-1-antitrypsin deficiency and liver disease are discussed.
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PMID:Alpha-1-antitrypsin deficiency: rare cause of adult cirrhosis--a case report. 842 51

alpha 1-Antitrypsin (AT) is the principal serum inhibitor of proteolytic enzymes such as neutrophil elastase. AT can exist as over 90 different genetically determined variants known as the Pi system; the three most important variants are type M (90% of population) and types S and Z, two of the commoner abnormal variants. Homozygotes of type Z have a severe reduction in the serum AT concentration and may develop pulmonary emphysema or hepatic cirrhosis. Heterozygotes of type SZ have a less severe reduction in serum AT concentration and the association with clinical disease is less clear. The S and Z variants are found mainly among those of European stock. The gene frequency for Pi type Z is highest on the north-western seaboard of the continent and the mutation seems likely to have arisen in southern Scandinavia. The distribution of type S is quite different; the gene frequency is highest in the Iberian peninsula and the mutation is likely to have arisen in that region. A population survey for determining the number of type Z homozygotes in a given community is important for planning purposes now that AT replacement therapy is potentially available.
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PMID:Alpha 1-antitrypsin deficiency in Europe: geographical distribution of Pi types S and Z. 1190 55

Thrombomodulin is a glycoprotein that can bind to thrombin and activate protein C, thus mitigating the effects of cytokines produced by inflammatory and immunological processes. The molecule exerts a protective function on endothelial cells. Thrombomodulin is cleaved to its soluble form by neutrophil elastase and by other substances produced during acute and chronic inflammatory responses, immunologic reactions and complement activation. ELISA technique yields normal serum levels of 3.1 +/- 1.3 ng/ml; in males these levels are higher; TM levels also rise during menopause. Other circumstances associated with an increase of serum TM levels are smoking, disseminated intravascular coagulation (DIC), cardiac surgery, atherosclerosis, ARDS, liver cirrhosis, diabetes mellitus, cerebral and myocardial infarction, and multiple sclerosis. Serum levels of TM represent an useful prognostic index, because they are associated with an increase in mortality rate, or however a progression of the underlying pathological condition.
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PMID:Clinical importance of thrombomodulin serum levels. 1155 26

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


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