Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0034067 (emphysema)
 11,506 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Proteinase-antiproteinase imbalances are recognized in several diseases including the two most common lethal hereditary disorders of white populations, alpha(1)-antitrypsin (alpha(1)-AT) deficiency and cystic fibrosis (CF). In alpha(1)-AT deficiency, the type Z variant of alpha(1)-AT forms polymers in the endoplasmic reticulum of hepatocytes resulting in liver disease in childhood. The block in alpha(1)-AT processing in hepatocytes significantly reduces levels of circulating alpha(1)-AT. This may lead in young adults to panacinar emphysema due to insufficient protection of the lower respiratory tract from neutrophil elastase, permitting progressive destruction of the alveoli. In CF, chronic bacterial lung infections due to impaired mucociliary clearance lead to a vigorous influx of neutrophils in the airways. Released levels of neutrophil serine proteinases, particularly elastase, exceed the antiproteinase capacity of endogenous serine proteinase inhibitors in the airways. Progressive proteolytic impairment of multiple defense pathways in addition to endobronchial obstruction and airway wall destruction are thought to be responsible for the reduced life expectancy in CF patients. Strategies to augment the antiproteinase defenses in the airways of patients with severe alpha(1)-AT deficiency or CF include the intravenous or aerosol administration of serine proteinase inhibitors. Studies in both patient groups using plasma-derived or transgenic alpha(1)-AT, recombinant secretory leukoprotease inhibitor or synthetic elastase inhibitors show promising results concerning drug safety and efficacy.
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PMID:Serine proteinase inhibitor therapy in alpha(1)-antitrypsin inhibitor deficiency and cystic fibrosis. 1053 68

Alpha1-antitrypsin deficiency, which can lead to both emphysema and liver disease, is a result of the accumulation of alpha1-antitrypsin polymers within the hepatocyte. A wealth of biochemical and biophysical data suggests that alpha1-antitrypsin polymers form via insertion of residues from the reactive center loop of one molecule into the beta-sheet of another. However, this long-standing hypothesis has not been confirmed by direct structural evidence. Here, we describe the first crystallographic evidence of a beta-strand linked polymer form of alpha1-antitrypsin: the crystal structure of a cleaved alpha1-antitrypsin polymer.
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PMID:Cleaved antitrypsin polymers at atomic resolution. 1071 94

A WHO expert group recommends neonatal screening for alpha1-antitrypsin deficiency (alpha1ATD). Homozygous alpha1ATD PiZZ occurs in 1 in 5000 of the U.S. Caucasian population and up to 1 in 500 individuals of the European population, with a large regional variation. It is a risk factor that predisposes mainly to liver disease in early infancy and emphysema in early adulthood. Most importantly, smoking decreases the duration of the asymptomatic phase and life expectancy by 10-20 y. The Swedish alpha1AT screening programme and subsequent information and advice prevented the majority of adolescents from starting to smoke. The involved parents and alpha1ATD adolescents retrospectively recommended neonatal screening. Potential advantages of neonatal alpha1AT screening are: early diagnosis and treatment of neonatal liver disease, optimal treatment of fever and bacterial infections theoretically preventing liver cell damage, genetic advice and information about the consequences of passive and active smoking. Potential advantages of postponing screening until age 11-12y are: identification of alpha1ATD close to the age when smoking may start, and possibility for the child to take part in the screening decision. Disadvantages of alpha1AT screening are: psychosocial reactions--the mother probably being most vulnerable in the neonatal period--and discrimination by insurance companies and employers. Important uncertainties are: lack of knowledge concerning participation in a voluntary alpha1AT screening, psychosocial reactions and the efficacy of anti-smoking advice if the information is given to school-age children and families. Thus the question whether and when to screen for alpha1ATD is still the topic of lively debate.
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PMID:A future for neonatal alpha1-antitrypsin screening? 1077 68

A WHO expert group recommends neonatal screening for alpha1-antitrypsin deficiency (alpha1ATD). Homozygous alpha1ATD PiZZ occurs in 1 in 5,000 of the U.S. Caucasian population and up to 1 in 500 individuals of the European population, with a large regional variation. It is a risk factor that predisposes mainly to liver disease in early infancy and emphysema in early adulthood. Most importantly, smoking decreases the duration of the asymptomatic phase and life expectancy by 10-20 y. The Swedish alpha1AT screening programme and subsequent information and advice prevented the majority of adolescents from starting to smoke. The involved parents and alpha1ATD adolescents retrospectively recommended neonatal screening. Potential advantages of neonatal alpha1AT screening are: early diagnosis and treatment of neonatal liver disease, optimal treatment of fever and bacterial infections theoretically preventing liver cell damage, genetic advice and information about the consequences of passive and active smoking. Potential advantages of postponing screening until age 11-12 y are: identification of alpha1ATD close to the age when smoking may start, and possibility for the child to take part in the screening decision. Disadvantages of alpha1AT screening are: psychosocial reactions-the mother probably being most vulnerable in the neonatal period-and discrimination by insurance companies and employers. Important uncertainties are: lack of knowledge concerning participation in a voluntary alpha1AT screening, psychosocial reactions and the efficacy of anti-smoking advice if the information is given to school-age children and families. Thus the question whether and when to screen for alpha1ATD is still the topic of lively debate.
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PMID:A future for neonatal alpha1-antitrypsin screening? 1091 52

The aim of this study was to investigate a group of severe alpha 1-antitrypsin deficient subjects. Of the 20 subjects detected, 7 were classified as Index Cases (discovered because they were symptomatic and had pulmonary emphysema or liver disease), while 13 were classified as Non-Index Cases (asymptomatic and discovered because they were relatives of Index Cases or because of the absence of alpha 1 band in serum electrophoresis). They underwent pulmonary function tests, determination of arterial blood gases, lung high resolution computed tomography and lung perfusion scan. All Index Cases were with the ZZ phenotype, indicating a major risk of developing related pulmonary emphysema or liver disease; most Index Cases (71%) were ex-smokers, while among the Non-Index Cases, 46% were smokers or ex-smokers, suggesting that smoking might be the main cofactor in the development of emphysema. Index Cases were older (statistical significance) and mostly male as compared with Non-Index Cases. A statistical significance was observed between the two groups for several lung function parameters (forced expiratory volume in one second, Tiffenau index, residual volume, diffusing capacity of the lung for carbon monoxide, arterial oxygen tension) as a result of a pathological impairment in Index Cases. This underdiagnosed condition merits more attention in order to prevent its complications and to get a better understanding about its diagnosis and management.
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PMID:[Severe alpha 1-antitrypsin deficiency: cross sectional clinical study]. 1092 May 2

alpha1-Antitrypsin (AAT) deficiency is a common inherited cause of emphysema and cirrhotic liver disease. Current laboratory diagnosis of Pi (proteinase inhibitor) status by protein analysis depends on the availability of blood samples and has a limited accuracy. Single-strand conformational polymorphism (SSCP) analysis and direct DNA sequencing can be performed from blood cells or from tissue samples, but it is a time-consuming procedure not suitable for screening purposes. We used a Light-Cycler assisted PCR approach to identify the PiZ mutation and to determine hetero- and homozygous carrier status from whole blood and from paraffin-embedded archival tissue specimens. The results were compared to those obtained by standard PCR amplification followed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR identified heterozygous PiZ mutations in 16 samples, a homozygous PiZ status in three cases, and wild-type PiM in five control samples. In all cases the results were confirmed by SSCP and direct DNA sequencing. Light-Cycler assisted PCR has a high detection rate for the PiZ mutation. It can be performed from blood or from fixed archival tissues, requires only small amounts of DNA, and allows a rapid diagnosis on a high output level.
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PMID:Rapid analysis of alpha1-antitrypsin PiZ genotype by a real-time PCR approach. 1093 83

Alpha1-antitrypsin (alpha1-AT) is the most abundant circulating inhibitor of serine proteases and therefore is essential to normal protease-anti-protease homeostasis. Inheritance of two parental alpha1-AT deficiency alleles is associated with a substantially increased risk for development of emphysema and liver disease. In very rare circumstances individuals may inherit alpha1-AT null alleles. Null alpha1-AT alleles are characterized by the total absence of serum alpha1-AT. These alleles represent the extreme end in a continuum of alleles associated with alpha1-AT deficiency. The molecular mechanisms responsible for absence of serum alpha1-AT include splicing abnormalities, deletion of alpha1-AT coding exons and premature stop codons. While these alleles comprise only a small proportion of alpha1-AT alleles associated with profound alpha1-AT deficiency, studies of their molecular mechanisms provide valuable insights into the structure, gene expression and intracellular transport of alpha1-AT.
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PMID:Molecular mechanisms of alpha1-antitrypsin null alleles. 1095 48

Alpha 1-antitrypsin deficiency is a genetically transmitted disorder associated with an increased risk of emphysema and liver disease. The highest incidence occurs in whites of Northern European descent; the disorder affects between 70,000 and 100,000 individuals in the United States. Most persons with alpha 1-antitrypsin deficiency are misdiagnosed or undiagnosed. The laboratory tests used to screen for and diagnose the disorder are simple, inexpensive, and provide an opportunity to prevent the development of clinical disease through education about cofactor avoidance. This article provides a review of the epidemiology, genetics, and clinical presentation of this disorder.
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PMID:Diagnosing alpha 1-antitrypsin deficiency. 1120 18

Alpha1-antitrypsin (alpha1AT) deficiency is a common lethal hereditary disorder of white persons of European descent. The condition is characterized by reduced serum levels of alpha1AT, a 52-kDa glycoprotein synthesized chiefly in the liver and, to a lesser extent, by macrophages and neutrophils. Alpha1AT acts as an antiprotease and is the physiological inhibitor of neutrophil serine proteases such as neutrophil elastase cathepsin G and proteinase 3. The clinical manifestations of alpha1AT deficiency occur chiefly in the lung, with a high risk of emphysema occurring by the third or fourth decade of life. Cigarette smoking accelerates the development of emphysema in persons with alpha1AT deficiency. There is also an increased risk of liver disease in alpha1AT deficiency, which occurs mostly in childhood. In this review, we will define further the diagnosis of alpha1AT deficiency and its clinical manifestations and describe the therapeutic strategies that are currently being developed to treat the hepatic and pulmonary disease associated with this condition.
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PMID:Alpha1-antitrypsin deficiency: biological answers to clinical questions. 1120 78

Alpha 1-antitrypsin deficiency is the most common genetic cause of liver disease in children. It is also associated with chronic liver disease, hepatocellular carcinoma, and pulmonary emphysema in adults. Liver injury is caused by hepatotoxic effects of retention of the mutant alpha 1-antitrypsin molecule within the endoplasmic reticulum of liver cells, and emphysema is caused by uninhibited proteolytic damage to elastic tissue in the lung parenchyma. Recent studies of the biochemistry and cell biology of the mutant alpha 1-antitrypsin molecule have led to advances in understanding susceptibility to liver injury and in developing new strategies for prevention of both liver and lung disease.
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PMID:Liver injury in alpha 1-antitrypsin deficiency. 1123 97


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