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)

To assess the pathological changes in the lungs and liver of 42 individuals who died while enrolled in the Registry of Individuals with Severe Deficiency of Alpha-1 Antitrypsin (AAT), all available histopathologic surgical or postmortem-derived specimens were reviewed by the pathologist member of the Death Review Committee. The underlying cause of death was emphysema in 34 patients and cirrhosis in 2 patients. Slides of lung were graded for emphysema, and liver specimens were graded for fibrosis, using respective pictorial scoring systems. Correlations between the degree of pathological abnormality and clinical features were evaluated. All lungs exhibited severe panacinar emphysema (mean emphysema score, 7.9 +/- 1.06 [standard deviation], where 10 represents the greatest severity) with a lower lobe predominance. Centriacinar emphysema was minimal. No correlation was found between the pathological severity of emphysema and pulmonary function measurements, and no significant correlation was found between the degree of emphysema and the degree of hepatic fibrosis. Mildly increased bronchial gland-to-wall ratio accompanied mild inflammation and goblet cell hyperplasia. There were minimal changes in small airways. Dilatation of membranous bronchioles was a frequent finding; however, bronchiectasis of larger airways was a minor feature in only 6 patients (15%). Airway morphological features did not correlate with the clinical presence of chronic bronchitis or asthma. Although the lack of correlation between liver and lung pathological changes may reflect different pathogenetic mechanisms of liver disease and lung disease, the lack of correlation between emphysema grade and lung function likely reflects the skewed sample in a series of patients with advanced lung disease.
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PMID:The bronchopulmonary pathology of alpha-1 antitrypsin (AAT) deficiency: findings of the Death Review Committee of the national registry for individuals with Severe Deficiency of Alpha-1 Antitrypsin. 1561

Alpha 1-antitrypsin (AAT) deficiency is a genetic disorder that is associated with emphysema and liver disease because of mutations in the protease inhibitor (PI) gene. Although AAT deficiency is known to be an autosomal recessive disorder, some heterozygous individuals have been found to be affected. In this study, a polymorphism-based approach was used to study the expression status of the PI gene in humans, sheep, and cattle. RT-PCR products obtained from a total of 141 tissues were analyzed by direct sequencing and RFLP. Genomic DNA and cDNA from saliva from human individuals, including a family of four and two families of two, were sequenced. Thirteen individuals showed biallelic expression, and three individuals showed monoallelic expression. This differential expression of the PI gene might elucidate the puzzling heterozygote controversy in which heterozygotes have been found to be affected with AAT deficiency. Sheep and cattle tissues showed a complex pattern of expression. In most sheep tissues (17/25), PI transcripts were expressed from both parental alleles; in three tissues, PI transcripts were expressed preferentially from one allele and partially expressed from the other allele; in eight tissues, PI transcripts were monoallelically expressed. Comparisons of the expression patterns of cattle fetuses and their dams show that the PI gene is biallelically expressed in fetuses and predominantly monoallelically expressed in the dams. The expression analysis of the bovine PI transcripts in the different tissues demonstrated sporadic pattern of expression with preferential monoalleleic expression for some tissues and preferential biallelic expression for other tissues.
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PMID:Monoallelic expression of the protease inhibitor gene in humans, sheep, and cattle. 1567 33

Alpha1-antitrypsin deficiency is a genetic disorder that affects about one in 2000-5000 individuals. It is clinically characterised by liver disease and early-onset emphysema. Although alpha1 antitrypsin is mainly produced in the liver, its main function is to protect the lung against proteolytic damage from neutrophil elastase. The most frequent mutation that causes severe alpha1-antitrypsin deficiency arises in the SERPINA 1 gene and gives rise to the Z allele. This mutation reduces concentrations in serum of alpha1 antitrypsin by retaining polymerised molecules within hepatocytes: an amount below the serum protective threshold of 11 micromol/L increases risk for emphysema. In addition to the usual treatments for emphysema, infusion of purified alpha1 antitrypsin from pooled human plasma represents a specific treatment and raises the concentrations in serum and epithelial-lining fluid above the protective threshold. Evidence suggests that this approach is safe, slows the decline of lung function, could reduce infection rates, and might enhance survival. However, uncertainty about the cost-effectiveness of this expensive treatment remains.
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PMID:Alpha1-antitrypsin deficiency. 1597 31

Alpha-1-antitrypsin deficiency is a genetic disorder that presents as early-onset emphysema in its most severe form. A high index of clinical suspicion is needed in cases of lung or liver disease of unknown etiology or a suggestive history and physical examination. Low or absent serum levels of alpha-1-antitrypsin levels identify persons with the disease and phenotyping is the confirmatory test. The main goal of management is attempting to prevent or slowing the progression of damage to the lungs. Medical and surgical options for treatment include augmentation therapy that maintains protective levels of AAT in the lung and serum and lung transplantation may be necessary in severe cases. We present this case report of a patient with Alpha-1-antitrypsin deficiency in order to increase awareness of this condition since early diagnosis improves long-term prognosis and reduces the overall cost of therapy.
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PMID:A diagnostic dilemma: case study of a 36-year-old female with alpha-1-antitrypsin deficiency. 1604 92

Alpha1-antitrypsin (AAT) deficiency is an underrecognized inherited disorder with pulmonary and hepatic implications for both adults and neonates. Clinical expressions of AAT deficiency are seen in the lung, liver, and the skin, with considerable variability in the severity of clinical disease. AAT deficiency accounts for nearly 3% of all cases of chronic obstructive pulmonary disease and is responsible for early-onset emphysema in nonsmokers. Ten to twenty percent of affected neonates develop significant liver disease. Panniculitis, a rare skin complication of AAT deficiency, is characterized by acute inflammatory infiltrate and fat necrosis. While we concentrate on the pulmonary aspect of AAT deficiency, we have included discussion of liver disease and panniculitis. Critical care and advanced practice nurses will benefit from gaining a better understanding of the causes, pathophysiology, diagnosis, and treatment of this disorder.
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PMID:Alpha1-antitrypsin deficiency: incidence and implications. 1632 7

Alpha-1-antitrypsin deficiency is a relatively common but under-recognized genetic disease in which individuals homozygous for the mutant Z disease-associated allele are at risk for the development of liver disease and emphysema. The protein product of the mutant Z gene is synthesized in hepatocytes but accumulates intracellularly rather than being appropriately secreted. The downstream effects of the intracellular accumulation of the mutant Z protein include the formation of unique protein polymers, activation of autophagy, mitochondrial injury, endoplasmic reticulum stress, and caspase activation, which subsequently progress in a cascade, causing chronic hepatocellular injury. The variable clinical presentations among affected individuals suggest an important contribution of genetic and environmental disease modifiers, which are only now being identified. The heterozygous carrier state for the mutant Z gene, found in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.
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PMID:Alpha-1-antitrypsin deficiency: diagnosis, pathophysiology, and management. 1651 30

Alpha-1-antitrypsin (AAT) is a serine protease inhibitor whose deficiency could cause emphysema and liver disease and, as recently described, could be a risk factor for lung cancer development. Alpha-1-antitrypsin inhibits a variety of proteases but its primary target is neutrophil elastase, an extracellular endopeptidase capable of degrading most protein components of the extracellular matrix. Inhibition of neutrophil elastase by AAT has an important role in maintaining the integrity of connective tissue. The gene encoding for AAT spans over 12.2 kb, consists of seven exons and is highly polymorphic. Therefore several methods for mutation screening of alpha-1-antitrypsin gene have been developed. Method described here is based on denaturing gradient gel electrophoresis (DGGE). This method is highly efficient and reliable and allows rapid analysis of entire coding region of alpha-1-antitrypsin gene, including splice junction sites. Previously described DGGE based analysis of AAT gene included overnight electrophoresis of individually amplified fragments. The optimization of the method described in this paper is directed towards the shortening of the duration of electrophoresis and amplification of fragments in multiplex reaction in order to make the analysis less time-consuming and therefore more efficient.
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PMID:Screening of alpha-1-antitrypsin gene by denaturing gradient gel electrophoresis (DGGE). 1681 90

In the classical form of alpha-1-antitrypsin (AT) deficiency a point mutation renders aggregation-prone properties on a hepatic secretory protein. The mutant ATZ protein in retained in the endoplasmic reticulum (ER) of liver cells rather than secreted into the blood and body fluids where it ordinarily functions as an inhibitor of neutrophil proteases. A loss-of-function mechanism allows the neutrophil proteases to slowly destroy the connective tissue matrix of the lung, resulting in premature development of pulmonary emphysema as early as the third decade of life. A gain-of-toxic function mechanism is responsible for liver inflammation and carcinogenesis. Indeed this deficiency is the most common genetic cause of liver disease in children in the US. It also causes chronic liver inflammation and carcinoma that manifests itself later in life. However, the majority of affected homozygotes apparently escape liver disease. This last observation has led to the concept that genetic and/or environmental modifiers affect the disposal of mutant ATZ within the ER or affect the protective cellular responses activated by accumulation of ATZ in the ER and, in turn, these modifiers determine which homozygotes develop liver inflammation and carcinoma. In this article I review a series of studies published over the last six years showing that autophagy is specifically activated by ER accumulation of ATZ and that it plays a critical role in the disposal of this mutant protein. Indeed, the most recent studies suggest that there is specialization of the autophagic pathway in that it is specifically activated by, and designed for disposal of, the aggregated forms of ATZ while the proteasome is specialized for disposal of soluble forms of ATZ. Together, these studies provide further evidence for the importance of autophagy in the cellular adaptive response to aggregated proteins in general.
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PMID:The role of autophagy in alpha-1-antitrypsin deficiency: a specific cellular response in genetic diseases associated with aggregation-prone proteins. 1687 89

Alpha-1 antitrypsin (AAT) deficiency is a common but under-recognized disease. This hereditary disorder is characterized by low levels of AAT, and increased risks of panacinar emphysema at an early age, liver disease, vasculitis and panniculitis. Destruction of lung parenchyma and consequent emphysema result from an imbalance between different inflammatory proteases (in particular, leukocyte elastase), and the major natural antiprotease, AAT. To offer a review of key aspects of this important condition, we present the epidemiology, natural history, and pathogenesis of AAT deficiency and, in the context of recent data and the publication of an international standards document regarding the diagnosis and management of individuals with AAT deficiency, review current therapy of AAT deficiency.
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PMID:A review of alpha-1 antitrypsin deficiency. 1713 53

Alpha (1)-antitrypsin deficiency is a common genetic disease in which individuals homozygous for the mutant Z allele are at risk for the development of liver disease and emphysema. The mutant Z protein product is synthesized in hepatocytes but then accumulates intracellularly rather then being appropriately secreted. The effects of the intracellular accumulation of the mutant Z protein in the liver include the formation of protein polymers, activation of autophagy, mitochondrial injury, and caspase activation, which progress in a cascade causing hepatocellular injury. Liver disease can occur at any age, although the majority of children are free of significant liver dysfunction. The variable clinical presentations suggest an important contribution of genetic and environmental disease modifiers. The heterozygous carrier state for the mutant Z gene, present in 1.5% to 3% of the population, is not itself a common cause of liver injury but may be a modifier gene for other liver diseases.
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PMID:Alpha1-antitrypsin deficiency in childhood. 1768 74


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