Lung function of school children with low levels of alpha1-antitrypsin and tobacco smoke exposure.
(49/411)
Exposure to environmental tobacco smoke (ETS) and other air pollutants has been associated with small decrements in lung function. The susceptibility to pollution exposure may, however, vary substantially between individuals. Children with an impaired protease-antiprotease balance may be particularly vulnerable. Therefore this study aimed to investigate the effects of ETS exposure on children with reduced levels of alpha1-antitrypsin (alpha1-AT). Random samples of school children (aged 9-11 yrs) (n=3,526) were studied according to the International Study of Asthma and Allergies in Childhood (ISAAC) phase II protocol, including parental questionnaires, pulmonary function and allergy testing. Blood samples were obtained to measure plasma levels of alpha1-AT and to genotype for pleomorphic protein inhibitor (Pi)Z and PiS alleles. Children with low levels of alpha1-AT (< or = 116 mg x dL(-1)) showed significant, albeit small decrements in baseline lung function. When exposed to ETS, pronounced decrements of pulmonary function, particularly in measures of mid- to end-expiratory flow rates, were seen in these children as compared to exposed children with normal levels of alpha1-AT. The mean levels of % predicted+/-SE in both groups were: maximum expiratory flow at 50% of vital capacity 79.4+/-7.2 versus 99.0+/-1.5, maximum expiratory flow at 25% of vital capacity 67.4+/-10.0 versus 100.3+/-2.1, maximal midexpiratory flow 73.7+/-8.6 versus 99.9+/-1.7. These findings suggest that school children with low levels of alpha1-antitrypsin are at risk of developing pronounced decrements in pulmonary function, particularly if they are exposed to environmental tobacco smoke. Parents of children with heterozygous alpha1-antitrypsin deficiency resulting in significantly reduced blood concentrations should be advised to prevent their children from being exposed to environmental tobacco smoke and dissuade them from taking up smoking. (+info)
Respiratory symptoms and lung function in young adults with severe alpha(1)-antitrypsin deficiency (PiZZ).
(50/411)
BACKGROUND: Neonatal screening for alpha(1)-antitrypsin (AAT) deficiency was undertaken in Sweden between 1972 and 1974 when 129 infants with severe AAT deficiency (phenotype PiZ) were identified. The cohort has been followed up prospectively. METHODS: 124 PiZ subjects, still alive and still living in Sweden, were invited to a follow up examination at about 22 years of age. The check up included a clinical examination, spirometric tests, and a questionnaire on smoking habits and respiratory symptoms. RESULTS: Ninety eight subjects (97 PiZZ and 1 PiZ-) subjects attended the follow up. The mean age of the subjects was 22.5 years (range 19.8-24.8). The mean (SD) forced expiratory volume in 1 second (FEV(1)) was 98 (14)% predicted, vital capacity (VC) was 103 (14)% predicted, and the mean FEV(1)/VC ratio was 83 (7)%. Eighty six subjects had previously undergone spirometric tests. The median follow up time was 4.3 years (range 0.9-7.3). The mean annual change in FEV(1) (% predicted) was -1.2% (95% CI -2.1 to -0.3), in VC (% predicted) was -1.5% (95% CI -2.0 to -0.9), and in the FEV(1)/VC ratio (%) was -0.3% (95% CI -0.7 to 0.2). Twenty eight individuals (29%) reported recurrent wheezing. Fifteen subjects (15%) had been diagnosed by a physician as having asthma. Eighteen subjects reported that they had smoked at some time; 10 were current smokers. The mean number of pack years among the ever smokers was 3.4 (range 0.6-10.5). Ten of 18 ever-smokers and 18 of 80 non-smokers reported recurrent wheezing (p<0.01), while exertional dyspnoea was reported by six ever smokers and 11 non-smokers (p<0.05). Lung function test results did not differ significantly between ever smokers and non-smokers. CONCLUSIONS: Young PiZ adults have essentially normal lung function, but have a high prevalence of asthma symptoms. Smoking in these individuals is associated with an increased frequency of respiratory symptoms. (+info)
Sputum chemotactic activity in chronic obstructive pulmonary disease: effect of alpha(1)-antitrypsin deficiency and the role of leukotriene B(4) and interleukin 8.
(51/411)
BACKGROUND: Neutrophil recruitment to the airway is thought to be an important component of continuing inflammation and progression of chronic obstructive pulmonary disease (COPD), particularly in the presence of severe alpha(1)-antitrypsin (alpha(1)-AT) deficiency. However, the chemoattractant nature of secretions from these patients has yet to be clarified. METHODS: The chemotactic activity of spontaneous sputum from patients with stable COPD, with (n=11) and without (n=11) alpha(1)-AT deficiency (PiZ), was assessed using the under-agarose assay. The contribution of leukotriene B(4) (LTB(4)) and interleukin 8 (IL-8) to the chemotactic activity was examined using an LTB(4) receptor antagonist (BIIL 315 ZW) and an IL-8 monoclonal antibody, respectively. RESULTS: Sputum neutrophil chemotactic activity (expressed as % n-formylmethionyl leucylphenylalanine (fMLP) control) was significantly higher in patients with alpha(1)-AT deficiency (mean (SE) 63.4 (8.9)% v 36.7 (5.5)%; mean difference 26.7% (95% CI 4.9 to 48.4), p<0.05). The mean (SE) contribution of both LTB(4) and IL-8 (expressed as % fMLP control) was also significantly higher in alpha(1)-AT deficient patients than in patients with COPD with normal levels of alpha(1)-AT (LTB(4): 31.9 (6.3)% v 18.0 (3.7)%; mean difference 13.9% (95% CI -1.4 to 29.1), p<0.05; IL-8: 24.1 (5.2)% v 8.1 (1.2)%; mean difference 15.9% (95% CI 4.7 to 27.2), p<0.05). When all the subjects were considered together the mean (SE) contribution of LTB(4) (expressed as % total chemotactic activity) was significantly higher than IL-8 (46.8 (3.5)% v 30.8 (4.6)%; mean difference 16.0% (95% CI 2.9 to 29.2), p<0.05). This difference was not significantly influenced by alpha(1)-AT phenotype (p=0.606). CONCLUSIONS: These results suggest that the bronchial secretions of COPD patients with alpha(1)-AT deficiency have increased neutrophil chemotactic activity. This relates to the increased levels of IL-8 and, in particular LTB(4), which accounted most of the sputum chemotactic activity in the patients with COPD as a whole. Increased chemotactic activity, together with inhibitor deficiency, may contribute to the more rapid disease progression seen in alpha(1)-AT deficiency via increased neutrophil recruitment and release of neutrophil elastase. (+info)
Chronic obstructive pulmonary disease. 1: Susceptibility factors for COPD the genotype-environment interaction.
(52/411)
Genetic factors including alpha(1)-antitrypsin deficiency are important in COPD. Candidate gene association studies in COPD are reviewed. Efforts to identify interactions between genetic factors and environmental determinants such as smoking may lead to improved understanding of the pathogenesis of the disease. (+info)
Screening for alpha1-Pi deficiency in patients with lung diseases.
(53/411)
In patients with pulmonary emphysema, studies have reported 2-3% of individuals with severe alpha1-Pi deficiency. The aims of this study were to evaluate the accuracy of a new method for quantifying alpha1-Pi through phenotyping from dried blood spots (DBS) and to test the hypothesis that the screening of a population at risk increases the detection rate for severe alpha1-Pi deficiency. The accuracy of phenotyping results from DBS was compared to conventional methods in a total of 555 individuals. In a prospective study 1,060 patients with chronic lung disease were screened for alpha1-Pi deficiency using DBS. The validation of the phenotyping method from DBS showed an accuracy of 100%. Out of 1,060 tested patients, none had a severe PiZ deficiency and only 3 had PiSZ, whilst 36 (3.34%) individuals were identified as heterozygous for PiMS and 39 (3.68%) for PiMZ. No patients with severe alpha1-Pi deficiency could be detected in this population and the frequency of PiMS or PiMZ detected was similar to that of the normal population. Thus, the screening of an unselected population of chronic obstructive pulmonary disease and asthma patients may not detect a large number of individuals with severe alpha1-Pi deficiency. (+info)
Fasting in alpha1-antitrypsin deficient liver: constitutive [correction of consultative] activation of autophagy.
(54/411)
Alpha1-antitrypsin (alpha1-AT) deficiency causes severe liver injury in a subgroup of patients. Liver injury is thought to be caused by retention of a polymerized mutant alpha1-ATZ molecule in the endoplasmic reticulum (ER) of hepatocytes and is associated with an intense autophagic response. However, there is limited information about what physiologic stressors might influence liver injury. In this study, we examined the effect of fasting in the PiZ mouse model of alpha1-AT deficiency, because fasting is a well-characterized physiological stressor and a known stimulus for autophagy. Results show that there is a marked increase in fat accumulation and in alpha1-AT-containing globules in the liver of the PiZ mouse induced by fasting. Although fasting induced a marked autophagic response in wild-type mice, the autophagic response was already activated in PiZ mice and did not further increase with fasting. PiZ mice also had a significantly decreased tolerance for prolonged fasting compared with wild-type mice (PiZ mice 0% survival of 72-h fast; wild-type 100% survivial). These results demonstrate an altered response to stress in the alpha1-AT-deficient liver, including inability to further increase an activated autophagic response, a developmental state-specific increase in alpha1-AT-containing globules, and increased mortality. (+info)
Low levels of nitric oxide and carbon monoxide in alpha 1-antitrypsin deficiency.
(55/411)
Quantitations of exhaled nitric oxide (NO) and carbon monoxide (CO) have been proposed as noninvasive markers of airway inflammation. We hypothesized that exhaled CO is increased in individuals with alpha(1)-antitrypsin (AT) deficiency, who have lung inflammation and injury related to oxidative and proteolytic processes. Nineteen individuals with alpha(1)-AT deficiency, 22 healthy controls, and 12 patients with non-alpha(1)-AT-deficient chronic obstructive pulmonary disease (COPD) had NO, CO, CO(2), and O(2) measured in exhaled breath. Individuals with alpha(1)-AT deficiency had lower levels of NO and CO than control or COPD individuals. Alpha(1)-AT-deficient and COPD patients had lower exhaled CO(2) than controls, although only alpha(1)-AT-deficient patients had higher exhaled O(2) than healthy controls. NO was correlated inversely with exhaled O(2) and directly with exhaled CO(2), supporting a role for NO in regulation of gas exchange. Exhaled gases were not significantly related to corticosteroid use or lung function. Demonstration of lower than normal CO and NO levels may be useful as an additional noninvasive method to evaluate alpha(1)-AT deficiency in individuals with a severe, early onset of obstructive lung disease. (+info)
Alpha1-antitrypsin deficiency: a report from the 2nd meeting of the Alpha One International Registry, Rapallo (Genoa, Italy), 2001.
(56/411)
The Alpha One International Registry is a scientific foundation established to comply with a World Health Organization recommendation to develop a multinational registry of alpha1-antitrypsin deficiency, with the aim of creating a common database of subjects recognised in a standardised way. A commitment of the Alpha One International Registry members, belonging to 15 national registries, is to meet every 2 yrs in an open scientific conference to provide a scientific and clinical update on the deficiency. The second Alpha One International Registry meeting was held in Rapallo (Genoa, Italy) on September 27th-28th, 2001, and 26 speakers provided an exhaustive overview of all aspects of alpha1-antitrypsin deficiency, including epidemiology, genetics, biochemistry, associated conditions, established and novel therapeutic options, and markers of efficacy. In the framework of a rare and often under-recognised condition, this meeting is likely to be central to improving understanding and increasing awareness of alpha1-antitrypsin deficiency. (+info)