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)

Alpha-1-antitrypsin deficiency (A1ATD) is one of the most common lethal hereditary disorders. Approximately 5 to 10% of the general population carry an "at risk" gene for the development of liver disease or emphysema of the lung. Patients with A1ATD associated liver disease constitute a histologically and clinically heterogeneous group. The pathogenesis of the disease still remains to be elucidated. Recent experimental evidence produced in the transgenic mouse model is in favour of the engorgement hypothesis considering the deposition of amorphous A1AT in the hepatocytes the prime event causing liver disease. This theory, however, fails to explain the clinical observation of the presence of a number of other factors known to cause chronic liver disease in A1ATD patients. The latter observation is in support of the deficiency theory, which explains the pathogenesis of emphysema of the lung, and would point to A1ATD as a predisposition to acquire chronic disease. The meaning of the increased synthesis of stress proteins in patients with liver disease is still speculative.
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PMID:[Pathogenesis of liver disease in alpha 1-antitrypsin deficiency]. 209 68

We have studied the clinical histories and liver biopsy findings in 1951 consecutive adult patients with suspected chronic liver disease, and in four known PiZ-homozygous alpha 1-antitrypsin-deficient patients with emphysema (candidates for lung transplant) and no known liver disease, in order to assess the importance of periportal alpha 1-antitrypsin granules in the liver and their possible causal role in liver disease, and to assess the value of possible screening tests. Periportal granules were found in 30 (1.5 per cent) of the 1951 liver biopsies and in all four known PiZ-homozygous subjects. They were the sole putative aetiological agent in eight of 85 patients (9.4 per cent) with otherwise cryptogenic cirrhosis and present in 2.5 per cent of patients with cirrhosis of known aetiology (alcohol, autoimmune etc.). All but one were Z phenotype (seven homozygotes, 22 heterozygotes). alpha 1-Antitrypsin granules were seen in 12 patients (including three of four lung transplant candidates) with no histological chronic liver disease. Determination of serum alpha 1-antitrypsin levels was quite unhelpful in identifying these patients. This study does not support the concept that periportal alpha 1-antitrypsin granules are necessarily pathogenic, but in some cases they may be causally related to otherwise cryptogenic liver disease. The presence of granules gave no important diagnostic, therapeutic or prognostic information.
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PMID:Alpha 1-antitrypsin granules in the liver--always important? 221 74

Individuals who are homozygous for the protease inhibitor phenotype Z (PiZ) genetic variant of alpha 1-antitrypsin (alpha 1-AT) have reduced plasma concentrations of alpha 1-AT, and are susceptible to premature development of pulmonary emphysema. A subset of this population develops chronic liver disease. The reduction in plasma concentrations of alpha 1-AT results from a selective defect in secretion as the abnormal PiZ alpha 1-AT protein accumulates within the cell. It has recently been shown in several experimental systems that the heat shock/stress response, a response characterized by the synthesis of a family of highly evolutionarily conserved proteins during thermal or chemical stress, may also be activated by the presence of abnormal proteins within the cell. Therefore, we predicted that the heat shock/stress response would be induced in the absence of thermal or chemical stress in alpha 1-AT-synthesizing cells of PiZZ individuals. In the following study, however, we show that net synthesis of proteins in the heat shock/stress gene family (SP90, SP70, ubiquitin) is increased only in a subset of the population, PiZZ individuals with liver disease. It is not significantly increased in PiZZ individuals with emphysema or in those without apparent tissue injury. Net synthesis of stress proteins is not increased in individuals with another variant of the alpha 1-AT gene (PiS alpha 1-AT) and is not increased in individuals with severe liver disease but a normal alpha 1-AT haplotype (PiM alpha 1-AT). These results demonstrate that the synthesis of stress proteins is increased in a subset of individuals with homozygous PiZZ alpha 1-AT deficiency, those also having liver disease.
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PMID:Synthesis of stress proteins is increased in individuals with homozygous PiZZ alpha 1-antitrypsin deficiency and liver disease. 255 76

Homozygous deficiency of alpha-1 antitrypsin is the most common inborn error or metabolism in Europe. Severe deficiency of this major protease inhibitor in serum is associated with chronic obstructive lung disease, chronic liver disease in adults and neonatal hepatitis. An overview is given of the role of heredity, and the diagnostic criteria and clinical and histological findings in this disorder. Emphysema seems to be caused by the free elastolytic activity of white cells, leading to the degradation of elastin. The pathophysiology of liver disease - less well understood - is discussed with special emphasis on the importance of heterozygous alpha-1 antitrypsin deficiency. Exogenous noxae seem to play an important role in the pathogenesis of heterozygous deficiency. In view of the 7% frequency of heterozygous alpha-1 antitrypsin deficiency in the European population and the role of noxae in the development of pulmonary and liver diseases, improved prophylaxis is mandatory.
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PMID:[Alpha 1-antitrypsin deficiency: a review with special reference to the significance of heterozygous deficiency]. 300 60

Hepatocytes are considered to be the predominant source of alpha 1-antitrypsin (AAT), the major antiprotease in human plasma. The development of emphysema in the hereditary PiZ AAT deficiency state suggests that inhibition of leukocyte elastase in the lung is a major function of this protein. In addition, patients with AAT deficiency are at increased risk for developing cholestasis in infancy and chronic liver disease as adults. The mechanism for hepatic cell injury, however, is not understood. Transgenic mice that express the normal human AAT gene demonstrate abundant AAT in hepatocytes and specific cell types of numerous nonhepatic tissues. Immunoperoxidase techniques have previously disclosed AAT in many of the cell types seen in transgenic mice; however, the issue of local synthesis vs. endocytosis in these cell types has remained unresolved. In this study, AAT mRNA was seen in a variety of tissues in the transgenic mouse. Immunoelectron microscopy of renal tubular and small intestinal epithelial cells in the transgenic mice demonstrated AAT within the cisternae of the rough endoplasmic reticulum, as in hepatocytes. These findings support the possibility of local synthesis in the various cell types. The results suggest that in addition to maintaining tissue integrity in the lung, the protease/antiprotease balance may have physiological functions in other organs as well.
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PMID:Multiple tissues express alpha 1-antitrypsin in transgenic mice and man. 326 Jun 5

The molecular structure and the serum levels of alpha 1-antitrypsin, the major antiprotease of human serum, are controlled by a series of codominant alleles at a single chromosomal locus, known as the Pi(protease-inhibitor) locus. The congenital deficiency of this inhibitor is known to be associated with the development of lung emphysema in early adulthood and chronic liver disease in childhood. Less frequent associations have been reported, such as rheumatoid arthritis, membranoproliferative glomerulonephritis and mosaicism for sex chromosomes. The identification of several suballeles of the Pi system, which was accomplished by means of a refinement of the isoelectric focusing technique, has promoted research concerning their possible pathogenic implications. The studies so far performed have often led to contradictory results, but nevertheless they strongly ascribe the property of controlling the quantitative levels of alpha 1-antitrypsin to certain M subtypes. Intermediate M3 subtype has recently been associated with the development of chronic obstructive lung disease in adulthood. Should this finding be confirmed by further evidence, a new approach to the prevention of lung disease could be considered, given that 30% of the individuals are carriers of the M3 suballele. In Italy, the incidence of congenital deficiency of alpha 1-trypsin appears to be greater in the northern regions, where 15-20 out of every 100,000 individuals are affected by the severe (ZZ) form of the deficiency.
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PMID:Serum protease inhibitory capacity. (Recent knowledge on alpha 1-antitrypsin deficiency). 629 Nov 23

Twenty-six different alleles have been identified for alpha 1 protease inhibitor (alpha 1 antitrypsin), each designated by a letter of the alphabet. In any individual two alleles codominantly determine the characteristics of alpha 1 protease inhibitor (Pi), including mobility on electrophoresis, serum concentration and acute phase response. Recent evidence has linked some mildly deficient phenotypes of Pi with a variety of chronic immunologic and inflammatory disorders, such as rheumatoid arthritis, juvenile chronic arthritis, systemic lupus erythematosus, ankylosing spondylitis, uveitis, asthma and fibrosing alveolitis, in addition to the well recognised association of severe deficiency with emphysema and chronic liver disease. This disease susceptibility in phenotypes associated with reduced serum levels may be due to alteration in lymphocyte responses, complement activation and leukocyte migration. Pi can also influence the autolytic effects of leukocytic enzymes on tissues and may inhibit some aspects of coagulation and fibrinolysis. Therefore patients with deficient Pi phenotypes are likely to have exaggerated immunologic and inflammatory responses.
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PMID:The role of alpha 1 protease inhibitor (alpha 1 antitrypsin) in the regulation of immunologic and inflammatory reactions. 696 57

Alpha-1-antitrypsin deficiency is a common autosomal recessive disorder associated with premature development of emphysema, liver cirrhosis and hepatocellular carcinoma. This article reviews the existing literature on alpha-1-antitrypsin deficiency, with an emphasis on recent developments. A description of the protein, gene structure and function of alpha-1-antitrypsin as well as clinical aspects are presented. Treatment issues are addressed and a framework for the diagnostic workup and management of patients with alpha-1-antitrypsin deficiency and chronic liver disease is provided.
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PMID:Alpha-1-antitrypsin deficiency and liver disease. 798 61

An association of alpha 1-antitrypsin deficiency with glomerulonephritis is rare and has so far been observed only in children or young adults. We report a 63-year-old man with severe alpha 1-antitrypsin deficiency associated with pulmonary emphysema, cirrhosis of the liver, and mesangioproliferative glomerulonephritis with nephrotic syndrome. Following initial presentation with nephropathy, further work-up revealed alpha 1-antitrypsin deficiency of proteinase inhibitor Z. In the absence of glomerular alpha 1-antitrypsin deposits the relationship between renal disease and alpha 1-antitrypsin deficiency remains unclear. alpha 1-Antitrypsin deficiency should be considered in adults with abnormal renal function and chronic liver disease.
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PMID:Glomerulonephritis as late manifestation of severe alpha 1-antitrypsin deficiency. 808 78

Alpha 1 antitrypsin deficiency (AT) is an autosomal recessive disease associated with chronic liver disease in adults and children and emphysema in adults. The disease is one of the most common inherited disorders of the Caucasian population of North Europe and North America and is the most common genetic reason for pediatric orthotopic liver transplantation (OLTx), although it is a rare indication in adults. The natural history of the disease is unpredictable and the pathogenesis of the liver injury unclear. Thirty-five patients with histologically apparent alpha 1 AT accumulation in the liver (22 adults, 13 children) have been transplanted in this center. Clinical features were correlated with the pretransplant phenotype, serum alpha 1 antitrypsin levels and potential precipitating factors. All children were PiZZ homozygotes, most of whom had presented with neonatal hepatitis. The majority of adult patients were heterozygotes presenting with portal hypertension and liver cirrhosis. Current one-year posttransplant survival figures are 73% for adults and 87.5% for children. Replacement of the cirrhotic liver results in acquisition of the donor phenotype, a rise in serum levels of alpha 1 antitrypsin, and apparent prevention of associated disease.
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PMID:Transplantation for end stage liver disease related to alpha 1 antitrypsin. 863 77


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