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Results for “Emphysema Phenotype”

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PubMed1989

Biochemical reaction of alpha 1 antitrypsin during the substitution therapy of patients with homozygote PI-ZZ deficit.

The homozygote deficit of alpha 1 antitrypsin (alpha 1 PI-ZZ) in patients frequently results in a premature development of emphysema in the lung due to incomplete protection against proteases. An active inhibitor substitution appears to be useful. The presented study proves the biological effect of alpha 1 antitrypsin infused into 8 patients. The results were an activity increase of leukocyte elastase and trypsin inhibition in serum as well as doubling of alpha 1 antitrypsin in sputum. This therapeutical conception (with a dose of 60 mg/kg body weight/week) results in an efficient protection. Inhibitors specific for mucosa are not influenced. An improvement of lung function during 6 weeks of intravenous therapy was not achieved. The progressive destruction of lung parenchyma can be probably prevented, however.

Adult↗
PubMed1988

Natural history of alpha-1-protease inhibitor deficiency.

Alpha-1-protease inhibitor (A1PI) exists in over 30 biochemical variants (the Pi system), inherited as autosomal codominant alleles. Homozygotes of Pi type Z have only 10 to 20 percent of the normal serum A1PI concentration and have a high risk of developing pulmonary emphysema. A1PI is an inactivator of polymorph lysosomal elastase, the unopposed action of which may damage the lung. Cigarette smoking is an important additional risk factor. Neonatal hepatitis occurs in 10 to 20 percent of Pi type Z persons, and cirrhosis develops in a number of them in later childhood or in adult life. In heterozygotes of Pi type MZ, pulmonary or hepatic disease may also develop, though they are at lesser risk than type Z homozygotes. Specific A1PI replacement therapy derived from human plasma is now available and has been administered to Pi type Z patients by weekly intravenous infusion without adverse effects. A controlled clinical trial would be desirable, though this would be attended by organizational and economic problems.

Arthritis, Rheumatoid↗
PubMed1992

High resolution computed tomography (HRCT) in emphysema associated with alpha-1-antitrypsin deficiency.

Alpha-1-antitrypsin (AAT) deficiency is an inherited disorder associated with an increased prevalence of pulmonary emphysema. To date there has been no description of the appearances on CT of the emphysema associated with AAT deficiency. We have reviewed the CT scans of 17 patients with proven AAT deficiency. Eleven out of 17 were examined with HRCT. The CT features were correlated with those on chest radiography. Areas of low density corresponding to parenchymal destruction and reduced perfusion, and attenuation of the pulmonary vasculature were present in all cases. Frank bulla formation occurred in 7/17 patients and was not a major feature. A striking CT finding was bronchial wall thickening and/or dilatation in 7/17 patients with gross cystic bronchiectasis in one patient. In contrast to appearances on chest radiography the upper zones were affected in all cases (17/17) and fine section scanning was particularly valuable in demonstrating changes in these less severely affected regions. Estimation of the extent of disease correlated well with abnormal lung function tests.

Adult↗
PubMed1995

Increased PiZ gene frequency for alpha 1 antitrypsin in patients with genetic haemochromatosis.

The putative relationship between genetic haemochromatosis and PiZ alpha 1 antitrypsin deficiency was studied using a monoclonal antibody against the PiZ variant in 67 consecutive patients with genetic haemochromatosis seen at Karolinska Hospital and Huddinge University Hospital, Stockholm over a 10 year period. Three (4.5%) of the patients with haemochromatosis were found to be PiZ homozygotes (odds ratio = 82, confidence interval = 26, 256; p < 0.0001). The prevalence of the heterozygous (PiZ) phenotype was similar to that in the general population (p = 0.937). During the ascertainment period, liver biopsy was performed in 65 (97%) of the patients; 66% (2 of 3) of the PiZ homozygotes were found to have cirrhosis compared with 10% (6/59) of the non-carriers of the PiZ variant (p = 0.039). None of the homozygous or heterozygous alpha 1 antitrypsin deficient patients had developed hepatocellular carcinoma compared with 3.4% (2 of 59) of the non-PiZ gene carriers (p = 1.0). Two of those with the homozygous phenotype had developed severe emphysema. HLA typing was performed in 18 patients, 16 (89%) of whom manifested antigens known to be linked to haemochromatosis. There were no significant differences between the PiZ gene carriers and non-carriers in mean age at onset of disease, sex distribution, or HLA type. Two of the PiZ heterozygotes had plasma alpha 1 antitrypsin concentrations below the normal range, though the group mean was lower than that of the non-PiZ carriers (p = 0.0003). The data suggest that the presence of the PiZ allele for alpha1 antitrypsin deficiency, in a double dose, is associated with genetic haemochromatosis and may contribute to the earlier onset of cirrhosis in these patients, though it does not increase the risk of hepatocellular carcinoma.

Adult↗
PubMed1996

Alpha-1-antitrypsin deficiency: biochemistry and clinical manifestations.

Alpha-1-antitrypsin (alpha 1-AT) deficiency is a well known cause of emphysema in adults. A subgroup of deficient individuals develops liver injury during infancy and childhood. In fact, it is the most common genetic cause of liver disease in children. Although lung injury is due to the decrease in alpha 1-AT function in the lung, allowing uninhibited elastolytic destruction of its connective tissue integrity, liver injury is probably due to retention of the mutant alpha 1-AT molecule in the endoplasmic reticulum (ER) of liver cells. Recent studies have shown that the mutant alpha 1-AT molecule polymerizes in the ER by a novel loop-sheet insertion mechanism. Other recent studies show that the subgroup of deficient individuals is susceptible to liver injury by virtue of unlinked genetic traits and/or environmental factors which interfere with degradation of the mutant alpha 1-AT molecules within the ER.

Adult↗
PubMed1985

Smoking, lung function, and alpha 1-antitrypsin deficiency.

From 1970 to 1983, 69 individuals (aged from infancy to 87 years) with homozygous alpha 1-antitrypsin deficiency (ZZ) were followed up. 12 had liver disease. Amongst the 33 patients with emphysema mean age of onset of dyspnoea in smokers (32 years) was significantly lower than that in non-smokers (51 years). Mean age at death (excluding that from liver disease) was 48 years in smokers and 67 in non-smokers. In non-smokers mean FEV1 was 77% of that predicted, but in smokers it was only 38% of that predicted. In non-smokers, FEV1 declined with age, but there was considerable individual variation. In smokers, the decline correlated with the extent of cigarette smoking in pack years. Mean decrease in FEV1 in non-smokers was abnormally high (80 ml/year), but significantly less than the massive mean decline of 317 ml/year in smokers. In ex-smokers the mean rate of decrease was 61 ml/year.

Adult↗
PubMed1988

Emphysema of early onset associated with a complete deficiency of alpha-1-antitrypsin (null homozygotes).

We have compared lung function in 3 subjects with no alpha 1-antitrypsin (alpha 1-protease inhibitor) (null homozygotes) with subjects having the typical deficiency, PIZZ. We identified a 31-yr-old woman, presenting with severe obstructive lung disease, who had no detectable plasma alpha 1-antitrypsin, indicating homozygosity for a "null" (or PI*QO) allele of alpha 1-antitrypsin. Two of her sisters have a similar deficiency, one with an onset of symptoms at 17 yr of age. Because of the likelihood that there are a number of different PI*QO alleles, the type in this family has been named null Mattawa (QOmattawa). All 3 homozygotes have shown a marked deterioration of lung function over a 7-yr period of follow-up. In contrast, lung function tests of 6 age-matched nonsmoking subjects with alpha 1-antitrypsin deficiency, PI type ZZ, showed no abnormalities of lung function. The 15 to 20% of the normal plasma concentration of alpha 1-antitrypsin associated with the PI*Z allele appears to provide some protection to the lung in comparison with a complete deficiency state.

Adult↗
PubMed1990

[Evaluation after 2 years of substitutive treatment of PiZZ emphysema with alpha-1 antitrypsin. 9 cases].

Homozygous PiZZ individuals with a serum deficiency due to a defect in the secretion of the alpha 1-antitrypsin protein are at risk of developing severe panlobular emphysema. Tobacco smokers are particularly exposed to the disease which begins at an earlier age. Treatment by substitutive therapy with alpha 1-antitrypsin concentrates seems to be the only possibility. A two years' clinical trial was performed in 9 PiZZ patients, with more than 1,500 infusions being administered weekly. Serum AAT levels were used as guidelines to follow biochemical changes in the protease-antiprotease balance. From 0.16 g/l initially, the AAT level rose to 0.57 g/l after 7 months. No adverse reaction was observed during the trial; the concentrated protein was well accepted, ant the antielastase activity of the protein recovered after injection was equivalent to the activity injected. An attempt to administer the infusions monthly was stopped when we observed a dramatic decrease of the serum AAT level. Clinically, stabilization of the symptoms was noted. No degradation was observed in the patients who took part in the trial, even if no real improvement was detected.

Adult↗
PubMed1979

Segregation distortion of the alpha 1-antitrypsin Pi Z allele.

alpha 1-antitrypsin (alpha 1AT) of the Pi type Z is associated with two diseases: pulmonary emphysema and cirrhosis of the liver. We report 23 families with both parents heterozygous for the PiZ allele, characterized from our own analysis and from world literature sources. All families were identified through members expressing disease. From the extended pedigrees, 18 backcross families (parents with Pi types MM and MZ) were identified. Analysis of the backcross families reveals a significant increase in Pi MZ offspring (.73) among families where the male is heterozygous. The distortion is not detected among families where the female is heterozygous. Among the matings where both parents are heterozygous, we found 0.43 Pi ZZ from families where one or more members expressed hepatic cirrhosis, and 0.40 Pi ZZ for total families studied. This contrasts to the 0.25 Pi ZZ expected, but is consistent with the distortion observed in backcross matings. The implications of various statistical approaches are discussed, and we point out why our findings differ from previous reports. We suggest a possible biological explanation residing in the fertilization process.

Alleles↗
PubMed1983

Can alpha-1-protease inhibitor be used in replacement therapy?

We propose that alpha-1-protease inhibitor (alpha 1 PI) can assume a major and beneficial role in preventing emphysema in alpha 1 PI-deficient individuals, and may also prove of value in the treatment of adult respiratory distress syndrome (ARDS). alpha 1 PI has a single, unusual disulfide bond that consists of a cysteine residue in the peptide chain covalently bound to a free amino acid cysteine. The linkage can be broken by reductants without adversely affecting the stability or the inhibitory activities of the protein. As a result of this property, alpha 1 PI can be effectively separated in solution from many other plasma proteins by salting out the contaminants in the presence of strong reductants. We have applied the technique of reductive-salting out, coupled with more conventional DEAE-anion exchange chromatography to isolate alpha 1 PI from Cohn Fraction IV-1, a relatively unused side product in the worldwide production of albumin and immunoglobulins. Furthermore, we have demonstrated that the product can be effectively pasteurized in the presence of various stabilizing additives. The necessary ingredients now exist for extensive clinical studies in the years ahead.

Chemical Phenomena↗
PubMed1998

[Long-term therapy of alpha 1-antitrypsin-deficiency-associated pulmonary emphysema with human alpha 1-antitrypsin].

alpha 1-antitrypsin (alpha 1-AT) deficiency is a genetic disorder characterized by low serum levels of alpha 1-AT and a high risk of pulmonary emphysema at a young age. The resulting surplus of proteases, mainly of neutrophil elastase, can be balanced by i.v. augmentation with alpha 1-AT. However, it is not clear if affected patients benefit from long-term augmentation therapy and no long-term safety data are available. We examined 443 patients with severe alpha 1-AT deficiency and pulmonary emphysema receiving weekly i.v. infusions of 60 mg/kg body weight alpha 1-AT in addition to their regular medication. The progression of the disease was assessed by repeated lung function measurements, particularly the decline in forced expiratory volume in 1 second (delta FEV1). 443 patients with alpha 1-AT deficiency tolerated augmentation therapy well with few adverse reactions. The delta FEV1 in 287 patients with available follow-up data was 57.1 +/- 31.1 ml per year. Stratified for baseline FEV1, the decline was 35.6 +/- 21.3 ml in the 108 patients with an initial FEV1 < 30% and 64.0 +/- 26.4 ml in the 164 with 30% < FEV1 < or = 65% of predicted normal (p = 0.0008). The remaining 15 patients had an initial FEV1 > 65%. Long-term treatment with i.v. alpha 1-antitrypsin in patients with severe alpha 1-Pi deficiency is feasible and safe. The decline in forced expiratory volume in one second is related to the initial forced expiratory volume in one second as in alpha 1-antitrypsin deficient patients not receiving augmentation therapy.

Adult↗
PubMed1988

[Substitution therapy with alpha-1-Pi in patients with alpha-1-Pi deficiency and progressive pulmonary edema].

In a multi-centre study 20 patients with severe congenital alpha-1-Pi deficiency and progressive pulmonary emphysema received infusions of alpha-1-Pi concentrate from human plasma once weekly for six months, at an initial dosage of 60 mg/kg body-weight, in some instances slightly increased to achieve a minimum serum level above 70 mg/100 ml. The immunologically measured serum level of alpha-1-Pi rose 30 min after start of the infusion by a mean of 130% of normal, at an initial level of 13%. An exponential fall followed this rise. The lowest level occurred at the end of the first week, immediately before the next infusion, to 35% of normal, a serum level which is assumed still to provide an effective protection against elastases in the lung. There was also a definite increase of free inhibitors against both trypsin and leucocyte-elastase in serum of all patients, with a minimal level which for both was many times that of the initial value. There were no side-effects in more than 500 infusions and no dose reduction was necessary. During the entire course there were no significant changes in haematological, coagulation and biochemical test results, and lung function means remained constant. No antibodies against alpha-1-Pi were demonstrated, nor transmission of hepatitis B.

Clinical Trials as Topic↗
PubMed2001

Longitudinal follow-up of patients with alpha(1)-protease inhibitor deficiency before and during therapy with IV alpha(1)-protease inhibitor.

BACKGROUND: The efficacy of IV augmentation therapy with human alpha(1)-protease inhibitor (alpha(1)-Pi) in patients with severe alpha(1)-Pi deficiency is still under debate. STUDY OBJECTIVES: To evaluate the progression of emphysema in patients with alpha(1)-Pi deficiency before and during a period in which they received treatment with alpha(1)-Pi. DESIGN: Multicenter, retrospective cohort study. SETTING: Outpatient clinics of 26 university clinics and pulmonary hospitals. PATIENTS: Ninety-six patients with severe alpha(1)-Pi deficiency receiving weekly augmentation therapy with human alpha(1)-Pi, 60 mg/kg of body weight, had a minimum of two lung function measurements before and two lung function measurements after augmentation therapy was started. Lung function data were followed up for a minimum of 12 months both before and during treatment (mean, 47.5 months and 50.2 months, respectively). MEASUREMENTS AND RESULTS: Patients were grouped according to the severity of their lung function impairment. The change in FEV(1) was compared during nontreatment and treatment periods. In the whole group, the decline in FEV(1) was significantly lower during the treatment period (49.2 mL/yr vs 34.2 mL/yr, p = 0.019). In patients with FEV(1) > 65%, IV alpha(1)-Pi treatment reduced the decline in FEV(1) by 73.6 mL/yr (p = 0.045). Seven individuals had a rapid decline of FEV(1) before treatment, and the loss in FEV(1) could be reduced from 256 mL/yr to 53 mL/yr (p = 0.001). CONCLUSION: Some patients with severe alpha(1)-Pi deficiency and well-preserved lung function show a rapid decline in FEV(1). These patients profit from weekly IV therapy with human alpha(1)-Pi and have less rapid decline if treated. Early detection of patients at risk and early start of augmentation therapy may prevent accelerated loss of lung tissue.

Cohort Studies↗
PubMed1992

Family study of alpha 1-antitrypsin deficiency: effects of cigarette smoking, measured genotype, and their interaction on pulmonary function and biochemical traits.

To gain insight into the variable expression of lung disease in alpha 1-antitrypsin (alpha 1AT) deficiency, five quantitative variables including forced expiratory volume at 1 sec (FEV1), forced expiratory flow rate between 25 and 75% of forced vital capacity (FEF25-75), total serum alpha 1AT, oxidized serum alpha 1AT, and total serum immunoglobulin E (IgE) were measured in alpha 1AT deficient individuals and their families. The effect of a known, measured genotype (the Pi type) was estimated for each quantitative trait; the influence of mode of case ascertainment on the measured genotype effect was also assessed. These analyses showed that total alpha 1AT levels are strongly influenced by Pi type; IgE levels are unaffected by Pi type; and FEV1, FEF25-75, and oxidized alpha 1AT are moderately influenced by Pi type. The effect of genotype-by-environment interaction between Pi type and pack-years of cigarette smoking on the five quantitative phenotypes was studied using an analysis of covariance. Significant Pi x pack-years interaction was evident for FEV1, but this effect is confounded in this data set with the Pi x age interaction. Probands who were ascertained because they had chronic obstructive pulmonary disease (COPD) do not demonstrate the significant Pi x pack-years interaction effect of the Pi x pack-years subjects ascertained for other reasons demonstrate. The effect of the Pi x pack-years interaction on FEV1 was no longer significant on a transformed scale, (FEVf12,) thus providing an additive scale for future data analysis. The increased sensitivity of Pi MZ individuals in our sample to cigarette smoking reduced the Pi x packs-years interaction effect on FEF25-75 to borderline significance. This investigation has provided an opportunity to incorporate both measured genotype and genotype-by-environment interaction analyses into the study of the variable expression of lung disease in Pi Z individuals.

Family↗
PubMedDate not supplied

Testing for differences in changes in the presence of censoring: parametric and non-parametric methods.

Some commonly used parametric and non-parametric methods for analysing repeated measures with incomplete observations are briefly reviewed. The performances of these methods in the presence of completely random, as well as informative censoring are compared in simulated experiments generated under the linear random effects model with parameter values derived from realistic examples. The effects of some moderate model deviations are also compared. The results indicate that in the presence of informative censoring, the usual parametric and nonparametric methods derived under the assumption of random censoring could either suffer severe loss of power or provide false positive results. The conditional linear model for informative censoring when used in conjunction with the bootstrap variance estimation procedure performed well under both random and informative censoring mechanisms. The non-parametric procedure obtained by ranking the individual summary statistics, although not as efficient as the conditional linear model with robust variance, also performed relatively well in most situations. Therefore, in situations in which informative censoring is likely to occur it is important to select the proper method of analysis to test for the informativeness of censoring and to account for its effects.

Bias↗
PubMed2000

In vivo klotho gene delivery protects against endothelial dysfunction in multiple risk factor syndrome.

The klotho gene, originally identified by insertional mutagenesis in mice, suppresses multiple aging phenotypes (e.g., arteriosclerosis, pulmonary emphysema, osteoporosis, infertility, and short life span). We have previously shown that mice heterozygous for a defect in the klotho gene upon parabiosis with wild-type mice show improved endothelial function, suggesting that the klotho gene product protects against endothelial dysfunction. In the present study, using the Otsuka Long-Evans Tokushima Fatty (OLETF) rat which demonstrates multiple atherogenic risk factors (e.g., hypertension, obesity, severe hyperglycemia, and hypertriglyceridemia) and is thus considered an experimental animal model of atherosclerotic disease, we show that adenovirus-mediated klotho gene delivery can (1) ameliorate vascular endothelial dysfunction, (2) increase nitric oxide production, (3) reduce elevated blood pressure, and (4) prevent medial hypertrophy and perivascular fibrosis. Based on these findings, klotho gene delivery improves endothelial dysfunction through a pathway involving nitric oxide, and is involved in modulating vascular function (e.g., hypertension and vascular remodeling). Our findings establish the basis for the therapeutic potential of klotho gene delivery in atherosclerotic disease.

Adenoviridae↗
PubMed1990

Criteria for alpha 1-antitrypsin substitution.

The pharmacology and safety of substitution treatment intravenously with alpha 1-antitrypsin (AAT) in patients deficient of AAT has been thoroughly investigated. The clinical efficacy of the treatment has so far not been established. The difficulties and uncertainties involved in defining the right persons for treatment, and determining the right time for a possible start of treatment are discussed. A controlled trail with participation of several European countries is suggested.

Adult↗