Alpha-1 Antitrypsin Deficiency Patients Research Articles

Alpha1-Antitrypsin-Mangel in Österreich: Auswertung der österreichischen Datenbank des internationalen Alpha1-Antitrypsin Registers

Alpha1-antitrypsin deficiency is a rare hereditary disorder. Deficient patients are at a higher risk to develop lung emphysema at an early age. The alpha1-antitrypsin registry was founded on 1996 to get new insights into the pathogenesis of the disease and to develop new therapeutic strategies. In this study the epidemiological and clinical findings of the Austrian alpha1-antitrypsin deficient patients are presented. A total of 139 patients with severe alpha1-antitrypsin deficiency, identified by phenol- and genotyping, were evaluated retrospectively by their physicians with the help of a questionnaire. Most patients were smokers or ex-smokers (71.9%) who developed symptoms in their fourth decade. The mean duration between the onset of symptoms and the final diagnosis was 6.5 years. About 25% of the evaluated patients were unable to practice their profession because of their illness. Alpha1-antitrypsin deficiency is a rare condition with delayed diagnosis. Because of the benefit of an early diagnosis further effort should be put towards early detection.

Pharmacokinetics of Subcutaneously Administered Alpha-1 Antitrypsin

RATIONALE: Alpha-1 Antitrypsin (AT) deficiency is treated with intravenous (IV) administration of pooled human AT (h-AT). IV infusions may be associated with hospitalization, venous access problems, hypersensitivity reactions and wide fluctuations in plasma AT levels. These drawbacks can be overcome if h-AT can be administered subcutaneously (SC). The feasibility of SC h-AT administration was investigated in rabbits using plasma pharmacokinetics as the end point. METHODS: h-AT was administered to naïve male New Zealand White rabbits by IV and SC routes either as single or multiple doses and plasma fractional availability measured up to 12 days post dosing. RESULTS: The plasma area-under-curve (AUC) at 200 mg/kg SC dose was 131 ± 13 h∗mg/ml (Mean ± SD), P < 0.01 compared to the IV group (179 ± 11). At 240 mg/kg SC dose, AUC (165 ± 21) was not significantly different compared to the 200 mg/kg IV group. In repeat-dose pharmacokinetics, AUC values at 50, 60 and 70 mg/kg were 79% (P < 0.05), 89% (NS) and 91% (NS) respectively compared to IV AUC at 50 mg/kg. Immunohistochemical staining of the lungs for h-AT in rabbits treated by SC route showed extensive localization of h-AT in the lung tissue. Histopathological evaluation of skin and underlying tissues at injection site did not reveal any inflammation complications. CONCLUSIONS: The results of this study suggest that pharmacokinetic parameters of SC administered h-AT are comparable to the IV administered h-AT when dosed at ≥120% of the IV dose (1:1.2). SC h-AT represents a viable alternate administration route in AT deficient patients.

Measurements of Desmosine and Isodesmosine by Mass Spectrometry in COPD

Application of mass spectrometry (MS) for direct measurements of desmosine (D) and isodesmosine (I) in urine, plasma, and sputum as markers of elastin degradation in patients with alpha(1)-antitrypsin deficiency (AATD) and non-AATD-related COPD. In COPD patients, the lungs undergo elastin injury, which can be monitored by measurements of D and I in body fluids as specific markers of elastin degradation using the specificity and sensitivity of MS. Acid hydrolysis of blood plasma, 24-h urine and sputum measurements, followed by chromatographic separation for mass spectrometric analysis. Each patient group had levels of plasma D and I that were statistically significantly higher than those of control subjects. AATD patients had higher levels than COPD patients with normal alpha(1)-antitrypsin (AAT) levels. Twenty-four-hour urine measurements demonstrated no significant difference in total levels of D and I among control subjects and patients but showed a free (unbound) concentration of D and I in urine, which was statistically significantly higher in patients with COPD with and without AAT. The D and I levels in the sputum of patients with AATD exceeded the levels in COPD patients with normal AAT levels. MS allows a sensitive and specific analysis of D and I in body fluids. The quantification of D and I in sputum, along with increases of D and I in plasma and an elevated free component of D and I in urine provide indexes that characterize patients with COPD and can be followed in relation to the course of the disease and/or therapy.

Estimating the Risk for Alpha-1 Antitrypsin Deficiency among COPD Patients: Evidence Supporting Targeted Screening

Alpha-1 antitrypsin deficiency is known as a significant genetic risk factor for COPD for carriers of phenotype PIMZ, and for phenotypes PIZZ and PISZ. Genetic epidemiological studies for alpha-1 antitrypsin deficiency conducted by others on both COPD patients and concurrent non-COPD controls were used to estimate the risk factors for all six phenotypic classes (namely, the normal phenotype PIMM, and the 5 deficiency allele phenotypes: PIMS, PIMZ, PISS, PISZ, and PIZZ). Studies on alpha-1 antitrypsin deficiency in white (Caucasian) COPD and non-COPD populations in 6 countries were combined to obtain estimates of the prevalence of the PIS and PIZ deficiency alleles in the combined COPD and non-COPD cohorts. The odds ratios for each of the six phenotypic classes of alpha-1 antitrypsin deficiency were calculated for a hypothetical population of 19.3 million white COPD patients in the United States of America. This approach demonstrated that 1,829,673 alpha-1 antitrypsin deficiency patients would be detected by testing 19.3 million white COPD patients and 536,033 in white non-COPD concurrent controls. The odds ratios for each of the phenotypic classes among white COPD patients demonstrate highly significant decreases in the normal phenotype PIMM, no significant change in the PIMS and PISS deficiency phenotypes, but highly significant increases in the prevalences of the PIMZ, PISZ, and PIZZ deficiency phenotypes. The result of the present study supports the concept of targeted screening for alpha-1 antitrypsin deficiency in countries with large populations of white (Caucasian) COPD patients.

Results of a case-detection programme for α1-antitrypsin deficiency in COPD patients

Alpha1-antitrypsin (alpha1-AT) deficiency is an underdiagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The present authors have conducted a nationwide case detection programme of alpha1-AT deficiency in unselected patients with COPD using dried blood spots. The first phase analysed samples from 971 patients by determining alpha1-AT concentrations and identifying the deficient Z allele by genotyping using rapid real-time PCR. The second phase analysed 1,166 samples with alpha1-AT concentrations and identified both the S and the Z allele, but only in samples with low alpha1-AT concentrations. A total of eight (0.37%) individuals with the severe deficiency PiZZ were detected. In addition, three patients were identified with the PiSZ genotype in the second phase (0.3%). The global cost of the programme was 41,512, which represents 19.42 per sample and 5,189 per PiZZ detected. A sensitivity analysis demonstrated that performing Z genotype to all samples would have resulted in increased costs of 28 per sample and 7,479.5 per PiZZ case identified. In conclusion, a case detection programme of alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood spots is feasible and at a reasonable cost per case detected. Diagnostic yield and costs depend largely on inclusion criteria and the protocol for processing of samples.

Environmental, occupational, and genetic risk factors for alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) deficiency is an inherited genetic disorder currently diagnosed in approximately 5,000 people in the United States. Although some individuals with AAT deficiency are asymptomatic, the condition often leads to deterioration of lung function in adults and is associated with emphysema, asthma, chronic obstructive pulmonary disease, and other respiratory diseases. In children, AAT deficiency can result in severe liver disease, including fatal cirrhosis in newborn infants. Although much is known about the clinical pathology of AAT deficiency, researchers are just beginning to characterize environmental, occupational, and genetic modifiers affecting the onset and progression of diseases related to AAT deficiency. On 19 August 2002, a group of basic scientists, clinicians, environmental health researchers, and public interest groups gathered at the National Institute of Environmental Health Sciences in Research Triangle Park, North Carolina, to discuss ongoing research on these topics. The goals of this workshop were to a) assess the present state of knowledge regarding environmental and occupational risk factors contributing to AAT deficiency morbidity and mortality, b) define future research needs in this area, and c) explore collaborative opportunities to advance understanding of risk factors affecting the progression of AAT deficiency-related disease. Participants agreed that new research initiatives in these areas represent an opportunity to benefit both basic science, through enhanced understanding of gene-environment interaction, and the AAT deficiency patient community, through innovative new approaches to disease management and treatment.

Decline in FEV1 in patients with PiZ alpha-1-antitrypsin deficiency: the Australian experience.

Alpha-1-antitrypsin (alpha1antitrypsin) deficiency is a rare hereditary disorder which characteristically presents with emphysema at an early age. The aim of the present study was to determine whether the rate of decline of lung function in alpha1antitrypsin-deficient subjects in Australia was similar to that found elsewhere. Patients registered with the Australian Alpha-1-Antitrypsin Replacement Program were studied. All patients (n = 50) had a serum alpha1antitrypsin concentration of < 0.3 g/L and had had spirometry measured over at least 2 years. They were compared with a group of normal volunteers (hospital staff, n = 107) with normal alpha1antitrypsin levels and phenotypes and with no clinical history of lung disease. All had spirometry measured for periods ranging from 2 to 6 years. The rate of decline of forced expiratory volume in 1 s (FEV1) for each subject was calculated by least squares linear regression using FEV1 against the time from entry into the study. The group mean (+/- SD) rate of decline in FEV1 was significantly greater (P < 0.01) in the alpha1antitrypsin-deficient patients (88 +/- 71 mL/year) than for the normal controls (-15 +/- 48 mL/year). There was no difference in decline in FEV1 when the data was analysed for gender and for index versus non-index cases. The results confirm previous reports of an accelerated rate of decline of FEV1 in patients with alpha1antitrypsin deficiency. Our results indicate that the rate of decline of lung function in alpha1antitrypsin deficient subjects in Australia is similar to that found in reported series from elsewhere.

Mutation detection in the alpha-1 antitrypsin gene (PI) using denaturing gradient gel electrophoresis.

A method for mutation detection in the alpha-1 antitrypsin gene (protease inhibitor 1; PI) has been developed using denaturing gradient gel electrophoresis of PCR amplified gene fragments. Using this experimental approach, all common phenotypes and mutations could be detected. Denaturing gradient gel electrophoresis (DGGE) was compared with standard isoelectric focusing (IEF) in 20 potential alpha1-antitrypsin deficient patients and their relatives. The genotype determined by DGGE was found to be more reliable in some cases than IEF, which is essential for a proper diagnosis of alpha-1 antitrypsin malfunctioning.

Airways obstruction and two year survival in patients with severe alpha 1-antitrypsin deficiency

Because of the limited number of donor organs available, the selection of patients for lung transplantation is crucial. One important issue in setting priorities is the life expectancy without transplantation. The purpose of this study was to estimate survival based on lung function, in alpha 1-antitrypsin deficient patients. Data from the Danish alpha 1-antitrypsin deficiency registry were analysed. The basic element of the analysis was two year intervals, characterized by date of spirometry and known mortality status 2 yrs later. We found a simple exponential relationship between lung function (forced expiratory volume one second (FEV1)) and two year survival on conservative treatment. The formula implies an almost 100% two year survival until FEV1 falls below one third of predicted normal; at this level two year mortality increases and will reach 50% at a FEV1 of 15% predicted. In conclusion, the two year mortality of emphysema patients due to alpha 1-antitrypsin deficiency increases exponentially with decreasing FEV1 and the results imply that only a few patients who underwent lung transplantation would have had a better two year prognosis without this procedure.

Heterozygous MZ alpha 1-antitrypsin deficiency in adults with chronic active hepatitis and cryptogenic cirrhosis.

To determine the prevalence of alpha 1-antitrypsin deficiency in patients with cirrhosis or chronic active hepatitis, we performed a five-year prospective study of liver-biopsy specimens from 1055 adults. Thirty-four patients whose specimens contained hepatocyte inclusions characteristic of the deficiency were phenotyped, and 25 had phenotype MZ (2.4 per cent). The distribution of patients with this phenotype among the 185 patients with cirrhosis diagnosed histologically was three of 84 patients with alcoholic cirrhosis (3.5 per cent), seven of 34 with non-B chronic active hepatitis (20.5 per cent), six of 28 with cryptogenic cirrhosis (21 per cent), and one of 39 with other kinds of cirrhosis (2.6 per cent). The increased prevalence of MZ in patients with cryptogenic cirrhosis and with chronic active hepatitis is highly significant (P < 0.001). Because serum levels of alpha 1-antitrypsin may be unreliable for identification of the subgroup of patients with chronic active hepatitis or cryptogenic cirrhosis, analysis of serum for the MZ phenotype and meticulous examination of biopsy specimens may be necessary.

Pathologic patterns of chronic obstructive pulmonary disease in patients with normal and deficient levels of alpha 1 antitrypsin

Twenty-nine patients with chronic obstructive pulmonary disease (COPD), selected on the basis of their alpha 1 antitrypsin (AAT) phenotype or trypsin inhibitory capacity (TIC), were studied by clinical and physiologic methods. Six were homozygous, 10 were heterozygous and 13 were normal with respect to their AAT levels. Spirometry, lung volume and diffusing capacity measurements indicated that the extent of pulmonary disease was greater in the patients with homozygous AAT deficiency as compared to the other groups. Quantitative measurements of regional ventilation and perfusion were made using xenon 133 and the results were evaluated by statistical technics. Two different methods of discriminant analysis of the regional ventilation and perfusion data clearly showed the three groups of patients to be significantly different from each other. Since the heterozygous AAT deficient patients had a pattern of disease which distinguished them from patients with both severely deficient and normal AAT levels, it is concluded that heterozygosity for AAT is an important factor in the development of COPD.