Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.6.1.1 (aspartate aminotransferase)
 21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Patients with homozygous (PiZ) alpha(1)-antitrypsin (AAT) deficiency have not only low baseline serum AAT levels (approximately 10 to 15% normal) but also an attenuated acute phase response. They are susceptible to the development of premature emphysema but may also be particularly susceptible to lung damage during bacterial exacerbations when there will be a significant neutrophil influx. The purposes of the present study were to assess the inflammatory nature of acute bacterial exacerbations of chronic obstructive pulmonary disease (COPD) in subjects with AAT deficiency, to compare this with COPD patients without deficiency, and to monitor the inflammatory process and its resolution following appropriate antibacterial therapy. At the start of the exacerbation, patients with AAT deficiency had lower sputum AAT (p < 0.001) and secretory leukoprotease inhibitor (SLPI; p = 0.02) with higher elastase activity (p = 0.02) compared with COPD patients without deficiency. Both groups had a comparable acute phase response as assessed by C-reactive protein (CRP) but the AAT-deficient patients had a minimal rise in serum AAT (to < 6 microM). After treatment with antibiotics, in patients with AAT deficiency, there were significant changes in many sputum proteins including a rise in SLPI levels, and a reduction in myeloperoxidase (MPO) and elastase activity (p < 0. 005 for all measures); the sputum chemoattractants interleukin-8 (IL-8) and leukotriene B(4) (LTB(4)) fell (p < 0.01), and protein leak (sputum/serum albumin ratio) became lower (p < 0.01). The changes were rapid and within 3 d of the commencement of antibiotic therapy the biochemical markers had decreased significantly, but took a variable time thereafter to return to baseline values. In conclusion, patients with AAT deficiency had evidence of increased elastase activity at the start of the exacerbation when compared with nondeficient COPD patients which probably reflects a deficient antiproteinase screen (lower sputum AAT and SLPI). The increased bronchial inflammation at presentation resolved rapidly with 14 d of antibiotic therapy.
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PMID:Evidence for excessive bronchial inflammation during an acute exacerbation of chronic obstructive pulmonary disease in patients with alpha(1)-antitrypsin deficiency (PiZ). 1058 15

Most individuals with AAT deficiency have escaped detection by healthcare systems worldwide. The large number of undiagnosed individuals has made it difficult to define the natural history of the clinical disease accurately, and severe ascertainment bias has colored the clinical descriptions of the disease. Most importantly, undetected individuals lose opportunities for important lifestyle changes and preventive therapies. To address this problem, the World Health Organization has recommended that all patients with chronic obstructive lung disease, and all adults and adolescents with asthma, be tested for AAT deficiency. Historically, the AAT Deficiency Detection Center has tested more than 30 000 individuals for the disease, and we have identified more than 1000 cases of AAT deficiency (approximately 30% of the known cases in the United States). Currently, we are implementing methods for determining AAT concentration (level), phenotype, and genotype in specimens of whole blood dried onto filter paper. This full spectrum of robust tests is performed on samples that are easily obtained and shipped to a central laboratory for processing. Wide application of these procedures may help to bring large numbers of presently undiagnosed patients to medical attention.
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PMID:Alpha1-antitrypsin deficiency: incidence and detection program. 1095 51

We evaluated the ability of intravenous supplementation therapy with alpha(1)-antitrypsin (AAT) to reduce the rate of urinary excretion of desmosine (DES), a specific marker of elastin degradation, in eight men and four women with emphysema due to severe, congenital deficiency of AAT (range 17-69 mg/dl). Nine were former cigarette smokers, two were current smokers, and one reported never smoking; their mean age was 54 (SD 12) yr and their mean FEV(1) was 41 (18%) of predicted. Urinary DES was measured by isotope dilution and HPLC. Prior to the start of AAT supplementation, mean DES excretion was 13.0 (5.0) microg/g creatinine, 73% higher than in healthy nonsmokers. During 8 wk of supplementation therapy, mean urinary DES excretion was 13.0 (5.9) microg/g creatinine, unchanged from the baseline period (p = 0.85 by repeated measures ANOVA). We conclude that baseline levels of elastin degradation in emphysematous patients with severe AAT deficiency were abnormally high and that 8 wk of AAT supplementation therapy did not appreciably reduce the rate of elastin degradation. These findings raise the possibilities that protective levels of AAT in the lungs are insufficient or that elastin degradation in the lungs of these subjects is not dependent upon neutrophil elastase at this time.
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PMID:Short-term supplementation therapy does not affect elastin degradation in severe alpha(1)-antitrypsin deficiency. The American-Italian AATD Study Group. 1111 16

Previous work from our group showed that recombinant adeno-associated virus (rAAV) vectors mediated long-term secretion of therapeutic serum levels of human alpha-1 antitrypsin (hAAT) after a single injection in murine muscle. We hypothesized that hepatocyte transduction could be even more efficient, since these cells represent the natural site of AAT production and secretion. To test this hypothesis, rAAV vectors containing the hAAT cDNA driven by either the human elongation factor 1 alpha promoter, the human cytomegalovirus immediate-early promoter (CMV), or the CMV-chicken beta actin hybrid (CB) promoter were injected into the portal or tail veins of adult C57Bl/6 mice. Potentially therapeutic serum levels of hAAT (600 microg/ml) were achieved after portal vein injection of doses of 4 x 10(9) infectious units (IU), a 10-fold lower dose than that required for similar levels of expression via the i.m. route. Serum levels greater than 1 mg/ml were achieved at doses of 3 x 10(10) IU. Southern blotting of liver DNA revealed the presence of circular episomal vector genomes. Immunostaining showed that transgene expression was scattered throughout the liver parenchyma. Similar results were obtained with a rAAV-CB-green fluorescent protein (GFP) vector. There was no evidence of hepatic toxicity. These data indicate that liver-directed rAAV-based gene therapy is effective in the murine model, and hence might be feasible for treatment of human AAT deficiency.
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PMID:Stable therapeutic serum levels of human alpha-1 antitrypsin (AAT) after portal vein injection of recombinant adeno-associated virus (rAAV) vectors. 1157 66

Alpha-1-antitrypsin deficiency (AAT deficiency) is one of the most common serious hereditary disorders in the world because it affects all major racial subgroups worldwide and there are at least 120.5 million carriers and deficient subjects worldwide. This genetic disease is related to a high risk for development of jaundice in infants, liver disease in children and adults, and pulmonary emphysema in adults. Moreover, AAT-deficiency carrier phenotypes (PiMS and PiMZ) and deficiency-allele phenotypes (PiSS, PiSZ, and PiZZ) are suspected to make subjects susceptible to a variety of other adverse health effects. As there is a limited database on the number of individuals affected by this disease worldwide, the authors of the present report collected data on control cohorts in genetic epidemiological studies published in the peer-reviewed literature worldwide. The data collected were used to estimate the numbers of carriers and deficiency-allele combinations for the two most common defective alleles, namely PiS and PiZ, in over 58 countries worldwide. The present report focuses on the distribution of the PiS and PiZ deficiency alleles in France, Italy, Portugal, and Spain. The total number of individuals at risk for adverse health effects were as follows: 9, 101, 739 in France; 4, 289, 566 in Italy; 2, 659, 241 in Portugal; and 8, 903, 773 in Spain. The geographical distribution of individual control cohorts and estimates of the numbers of carriers and deficiency-allele phenotypes in each of these four southern European countries are shown in individual tables and maps. This report will be followed by other reports on the remaining countries in Europe, as well as worldwide.
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PMID:Genetic epidemiology of alpha-1 antitrypsin deficiency in southern Europe: France, Italy, Portugal and Spain. 1278 56

A case of a 58-year-old woman with history of bilateral lung transplant secondary to alpha-1 antitrypsin deficiency (PIZZ), who presented with a severe drug-induced cholestasis secondary to prochlorperazine is reported. After 27 months of prochlorperazine use, she developed liver failure consisting of jaundice with ascites. Computed tomography of the abdomen, abdominal ultrasonography as well as an endoscopic retrograde cholangiopancreatography showed no evidence for biliary obstruction. Liver biopsy demonstrated diffuse ongoing advanced chronic cholestasis, moderate portal and periportal inflammation as well as bridging fibrosis. During her hospitalization, her total bilirubin increased to 38.6 mg/dL; alkaline phosphatase to 362 IU/L, alanine aminotransferase to 71 IU/L and aspartate aminotransferase to 88 IU/L. After several weeks of ursodiol therapy without clinical improvement the prochlorperazine was discontinued and was followed by a rapid improvement in her measures of liver injury. An immediate decline of her serum total bilirubin and alkaline phosphatase to 21.4 mg/dL and 258 IU/L, respectively, occurred strongly suggesting the idea of a prochlorperazine-induced injury.
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PMID:Prochlorperazine-induced cholestasis in a patient with alpha-1 antitrypsin deficiency. 1457 32

alpha(1)-Antitrypsin (AAT) deficiency is a common but under-recognised condition. Since its first description by Laurell and Eriksson in 1963, significant advances have been made in understanding the genetics, physiology and pathophysiology of this condition. The intravenous administration of purified AAT to AAT-deficient individuals has been shown to confer biochemical efficacy by raising the serum AAT level above an epidemiologically established 'protective threshold' while preserving the biochemical properties and functional capacity of the protease inhibitor. Although the lack of a large randomised controlled trial to date has precluded the definitive demonstration of clinical efficacy of intravenous AAT augmentation therapy, substantial evidence supporting its use in AAT-deficient individuals with moderate airflow obstruction has accumulated. For example, both large observational studies comparing rates of forced expiratory volume decline among recipients of augmentation therapy versus non-recipients have shown slower rates of decline among augmentation therapy recipients, especially those with moderately severe airflow obstruction. Also, some evidence suggests that use of augmentation therapy confers an anti-inflammatory effect. For example, a web-based survey suggested that recipients of augmentation therapy experienced fewer respiratory infections than non-recipients. Despite its high cost, intravenous AAT augmentation therapy remains the only US FDA-approved treatment option for patients with AAT deficiency. Research into new and evolving treatments is currently underway.
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PMID:Augmentation therapy for alpha(1)-antitrypsin deficiency. 1530 59

Alpha(1)-antitrypsin (AAT) deficiency is a genetic disorder that may cause serious pulmonary or liver impairment in children or adults. Although genetic sequencing of the AAT gene has only been available for 20 years, analysis of the amount and electrophoretic mobility of the AAT protein has allowed clinical phenotyping for more than 40 years. There have been no studies assessing the psychological impact of having a sib affected by AAT deficiency. Twenty-five participants drawn from the Alpha-1 Research Registry completed a questionnaire and semi-structured interview. Respondents were supportive of testing prior to adulthood for AAT status; 18 thought it was a good idea to test a child, three did not know, and four said children should not be tested, primarily citing insurance concerns. Of those 18 who stated it was a good idea, 14 would test at birth. Knowledge of genetics of AAT deficiency was limited; only 44% of respondents understood the inheritance pattern. We recommend: (1) parents and sibs need help in mourning the loss of children with AAT deficiency; young sibs are at risk for trauma and long-term developmental problems. (2) Teams evaluating donors for liver transplantation should be aggressive in ruling out AAT deficiency prior to invasive testing. (3) Testing should be offered to individuals with a family history of AAT deficiency to obtain the health benefits of lifestyle modification and limit the burden of disease discovery in symptomatic relatives. (4) Awareness of liver disease from AAT deficiency should be increased.
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PMID:"The lion, the witch and the wardrobe": impact on sibs of individuals with AAT deficiency. 1537 47

Severe alpha(1)-antitrypsin (AAT) deficiency is an inherited disorder that leads to the development of emphysema in smokers at a relatively young age; most are disabled in their forties. Emphysema is caused by the protease-antiprotease imbalance when smoking-induced release of neutrophil elastase in the lung is inadequately inhibited by the deficient levels of AAT, the major inhibitor of neutrophil elastase. This protease-antiprotease imbalance leads to proteolytic damage to lung connective tissue (primarily elastic fibers), and the development of panacinar emphysema. AAT replacement therapy, most often applied by weekly intravenous infusions of AAT purified from human plasma, has been used to partially correct the biochemical defect and raise the serum AAT level above a theoretically protective threshold level of 0.8 g/L. A randomized controlled clinical trial was not considered feasible when purified antitrypsin was released for clinical use. However, AAT replacement therapy has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. There was a suggestion of a slower progression of emphysema by computed tomography (CT) scan in a small randomized trial. Two nonrandomized studies comparing AAT-deficient patients already receiving replacement therapy with those not receiving it, and a retrospective study evaluating a decline in FEV(1) before and after replacement therapy, suggested a possible benefit for selected patients. Because of the lack of definitive proof of the clinical effectiveness of AAT replacement therapy and its cost, we recommend reserving AAT replacement therapy for deficient patients with impaired FEV(1) (35-65% of predicted value), who have quit smoking and are on optimal medical therapy but continue to show a rapid decline in FEV(1) after a period of observation of at least 18 months. A randomized placebo-controlled trial using CT scan as the primary outcome measure is required. Screening for AAT deficiency is recommended in patients with chronic irreversible airflow obstruction with atypical features such as early onset of disease or disability in their forties or fifties, or positive family history, and in immediate family members of patients with AAT deficiency.
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PMID:Emphysema in alpha1-antitrypsin deficiency: does replacement therapy affect outcome? 1572 45

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


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