Predicting Exacerbations in Alpha-1 Antitrypsin Deficiency Using Clinical and Pulmonary Function Tests: Portuguese EARCO Registry.

INTRODUCTION: Exacerbations are common in individuals with alpha-1 antitrypsin deficiency (AATD)-related lung disease. This study intended to identify independent predictive factors for exacerbations in AATD using the Portuguese European Alpha-1 Research Collaboration (EARCO) registry. METHODS: This study includes patients from the Portuguese EARCO registry, a prospective multicenter cohort (NCT04180319). From October 2020 to April 2023, this registry enrolled 137 patients, 14 of whom were excluded for analysis for either missing 12 months of follow-up or baseline pulmonary function. RESULTS: Among the 123 AATD patients, 27 (22.0%) had at least one exacerbation in the last 12 months of follow-up. Patients with Pi*ZZ phenotype were three times more likely than the rest of the population to experience any exacerbation (32.7 vs. 14.1%, p = 0.014; OR 3.0). BODE index was significantly higher in exacerbators than in non-exacerbators (3.9 ± 2.4 vs. 1.3 ± 1.2; p < 0.001), including on multivariate analysis (p = 0.002). Similar results were found for BODEx (multivariate p < 0.001). DLCO was the only functional parameter independently associated with exacerbations (p = 0.024). CONCLUSIONS: DLCO, BODE, and BODEx were independent predictors of exacerbations at 12 months in AATD patients. Understanding these risk factors can aid decision-making on AATD-related lung disease management and improve patient outcomes.

Severe α1-antitrypsin deficiency associated with lower blood pressure and reduced risk of ischemic heart disease: a cohort study of 91,540 individuals and a meta-analysis.

BACKGROUND: Increased elastase activity in α1-antitrypsin deficiency may affect elasticity of the arterial walls, and thereby blood pressure and susceptibility to cardiovascular disease. We hypothesized that severe α1-antitrypsin deficiency is associated with reduced blood pressure and susceptibility to cardiovascular disease. METHODS: We genotyped 91,353 adults randomly selected from the Danish general population and 187 patients from the Danish α1-Antitrypsin Deficiency Registry and recorded baseline blood pressure, baseline plasma lipids and cardiovascular events during follow-up. 185 participants carried the ZZ genotype, 207 carried the SZ genotype and 91,148 carried the MM genotype. RESULTS: α1-Antitrypsin deficiency was associated with decreases in blood pressure of up to 5 mmHg for systolic blood pressure and up to 2 mmHg for diastolic blood pressure, in ZZ vs SZ vs MM individuals (trend test, P's ≤ 0.01). Plasma triglycerides and remnant cholesterol were reduced in ZZ individuals compared with MM individuals (t-test, P's < 0.001). α1-Antitrypsin deficiency was associated with lower risk of myocardial infarction (trend test P = 0.03), but not with ischemic heart disease, ischemic cerebrovascular disease or hypertension (trend test, P's ≥ 0.59). However, when results for ischemic heart disease were summarized in meta-analysis with results from four previous studies, individuals with versus without α1-antitrypsin deficiency had an odds ratio for ischemic heart disease of 0.66 (95% CI:0.53-0.84). CONCLUSIONS: Individuals with severe α1-antitrypsin deficiency have lower systolic and diastolic blood pressure, lower plasma triglycerides and remnant cholesterol, reduced risk of myocardial infarction, and a 34% reduced risk of ischemic heart disease.

Heteropolymerization of α-1-antitrypsin mutants in cell models mimicking heterozygosity.

The most common genotype associated with severe α-1-antitrypsin deficiency (AATD) is the Z homozygote. The Z variant (Glu342Lys) of α-1-antitrypsin (AAT) undergoes a conformational change and is retained within the endoplasmic reticulum (ER) of hepatocytes leading to the formation of ordered polymeric chains and inclusion bodies. Accumulation of mutated protein predisposes to cirrhosis whilst plasma AAT deficiency leads to emphysema. Increased risk of liver and lung disease has also been reported in heterozygous subjects who carry Z in association with the milder S allele (Glu264Val) or even with wild-type M. However, it is unknown whether Z AAT can co-polymerize with other AAT variants in vivo. We co-expressed two AAT variants, each modified by a different tag, in cell models that replicate AAT deficiency. We used pull-down assays to investigate interactions between co-expressed variants and showed that Z AAT forms heteropolymers with S and with the rare Mmalton (Phe52del) and Mwurzburg (Pro369Ser) mutants, and to a lesser extent with the wild-type protein. Heteropolymers were recognized by the 2C1 mAb that binds to Z polymers in vivo. There was increased intracellular accumulation of AAT variants when co-expressed with Z AAT, suggesting a dominant negative effect of the Z allele. The molecular interactions between S and Z AAT were confirmed by confocal microscopy showing their colocalization within dilated ER cisternae and by positivity in Proximity Ligation Assays. These results provide the first evidence of intracellular co-polymerization of AAT mutants and contribute to understanding the risk of liver disease in SZ and MZ heterozygotes.

Alpha-1 Antitrypsin Deficiency and Pregnancy.

Alpha-1 Antitrypsin Deficiency (A1AD) is a hereditary condition characterized by low levels of circulating alpha-antitrypsin (AAT) in plasma. It is the best understood genetic risk factor for the development of chronic obstructive pulmonary disease (COPD). The diagnosis of A1AD is under-recognized. While there is a significant heterogeneity in disease presentation in relation to the severity of symptoms and prognosis, it is not uncommon for young individuals, including pregnant women to already have moderate to advanced lung disease at the time of diagnosis. Reductions in AAT levels may have unique implications for a gravid patient beyond that of lung disease. Care of the pregnant A1AD patient with chronic lung disease follows the principles of care for the management of airways disease in general with control of symptoms and reduction in exacerbation risk the main tenets of treatment. The effect of A1AD and augmentation in pregnancy has not been studied and thus care is reliant on expert opinion and clinical experience. Providers caring for pregnant patients with A1AD should consider referral to health care systems and providers with specific expertise in A1AD. Ultimately the decision is left to the individual patient and their physician to weigh the risk benefit of cessation or continuation of therapies. In this review, we present the perinatal course of a woman with A1AD and review the available literature pertaining to AAT and pregnancy and discuss the clinical implications.

Methods of Purification and Application Procedures of Alpha1 Antitrypsin: A Long-Lasting History.

The aim of the present report is to review the literature addressing the methods developed for the purification of alpha1-antitrypsin (AAT) from the 1950s to the present. AAT is a glycoprotein whose main function is to protect tissues from human neutrophil elastase (HNE) and other proteases released by neutrophils during an inflammatory state. The lack of this inhibitor in human serum is responsible for the onset of alpha1-antitrypsin deficiency (AATD), which is a severe genetic disorder that affects lungs in adults and for which there is currently no cure. Being used, under special circumstances, as a medical treatment of AATD in the so-called "replacement" therapy (consisting in the intravenous infusion of the missing protein), AAT is a molecule with a lot of therapeutic importance. For this reason, interest in AAT purification from human plasma or its production in a recombinant version has grown considerably in recent years. This article retraces all technological advances that allowed the manufacturers to move from a few micrograms of partially purified AAT to several grams of highly purified protein. Moreover, the chronic augmentation and maintenance therapy in individuals with emphysema due to congenital AAT deficiency (current applications in the clinical setting) is also presented.

Alpha-1 Antitrypsin-Deficient Macrophages Have Increased Matriptase-Mediated Proteolytic Activity.

Alpha-1 antitrypsin (AAT) deficiency-associated emphysema is largely attributed to insufficient inhibition of neutrophil elastase released from neutrophils. Correcting AAT levels using augmentation therapy only slows disease progression, and that suggests a more complex process of lung destruction. Because alveolar macrophages (Mɸ) express AAT, we propose that the expression and intracellular accumulation of mutated Z-AAT (the most common mutation) compromises Mɸ function and contributes to emphysema development. Extracellular matrix (ECM) degradation is a hallmark of emphysema pathology. In this study, Mɸ from individuals with Z-AAT (Z-Mɸ) have greater proteolytic activity on ECM than do normal Mɸ. This abnormal Z-Mɸ activity is not abrogated by supplementation with exogenous AAT and is likely the result of cellular dysfunction induced by intracellular accumulation of Z-AAT. Using pharmacologic inhibitors, we show that several classes of proteases are involved in matrix degradation by Z-Mɸ. Importantly, compared with normal Mɸ, the membrane-bound serine protease, matriptase, is present in Z-Mɸ at higher levels and contributes to their proteolytic activity on ECM. In addition, we identified matrix metalloproteinase (MMP)-14, a membrane-anchored metalloproteinase, as a novel substrate for matriptase, and showed that matriptase regulates the levels of MMP-14 on the cell surface. Thus, high levels of matriptase may contribute to increased ECM degradation by Z-Mɸ, both directly and through MMP-14 activation. In summary, the expression of Z-AAT in Mɸ confers increased proteolytic activity on ECM. This proteolytic activity is not rescued by exogenous AAT supplementation and could thus contribute to augmentation resistance in AAT deficiency-associated emphysema.

Survival in individuals with severe alpha 1-antitrypsin deficiency (PiZZ) in comparison to a general population with known smoking habits.

Knowledge about the natural history of severe alpha 1-antitrypsin (AAT) deficiency (PiZZ) is limited. Our aim was to compare the survival of PiZZ individuals with randomly selected controls from the Swedish general population.The PiZZ subjects (n=1585) were selected from the Swedish National AATD Register. The controls (n=5999) were randomly selected from the Swedish population register. Smoking habits were known for all subjects.Median follow-up times for the PiZZ subjects (731 never-smokers) and controls (3179 never-smokers) were 12 and 17 years, respectively (p<0.001). During follow-up, 473 PiZZ subjects (30%), and 747 controls (12%) died. The PiZZ subjects had a significantly shorter survival time than the controls, p<0.001. After adjustment for gender, age, smoking habits and presence of respiratory symptoms, the risk of death was still significantly higher for the PiZZ individuals than for the controls, hazard ratio (HR) 3.2 (95% CI 2.8-3.6; p<0.001). By contrast, the risk of death was not increased in never-smoking PiZZ individuals identified by screening, compared to never-smoking controls, HR 1.2 (95% CI 0.6-2.2).The never-smoking PiZZ individuals identified by screening had a similar life expectancy to the never-smokers in the Swedish general population. Early diagnosis of AAT deficiency is of utmost importance.

Maximal mid-expiratory flow detects early lung disease in α1-antitrypsin deficiency.

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α1-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk.Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV1), ratio of FEV1/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV1 were assessed in 196 AATD patients.FEV1/FVC, FEV1 % predicted and lung densitometry related to MMEF % pred (r2=0.778, p<0.0001; r2=0.787, p<0.0001; r2=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV1/FVC and MMEF (group 1), normal FEV1/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09-39.63) versus 9.67 (IQR 1.83-22.35); p=0.006) and had a greater subsequent decline in FEV1 (median change in FEV1 -1.09% pred per year (IQR -1.91-0.04% pred per year) versus -0.04% pred per year (IQR -0.67-0.03% pred per year); p=0.007).A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV1.

The prevalence of diagnosed α1-antitrypsin deficiency and its comorbidities: results from a large population-based database.

α1-Antitrypsin deficiency (AATD) is a genetically determined disorder that is associated with different clinical manifestations. We aimed to assess the prevalence of diagnosed AATD and its comorbidities using a large healthcare database.In this retrospective longitudinal observational study, we analysed data from 4 million insurants. Using International Classification of Diseases revision 10 (ICD-10) codes, we assessed the prevalence, comorbidities and healthcare utilisation of AATD patients (E88.0 repeatedly coded) relative to non-AATD patients with chronic obstructive pulmonary disease (COPD), emphysema or asthma.In our study population, we identified 673 AATD patients (590 aged ≥30 years), corresponding to a prevalence of 23.73 per 100 000 in all age groups and 29.36 per 100 000 in those ≥30 years. Based on the number of AATD cases detected in the sample size (673 out of 2 836 585), we extrapolated that there were 19 162 AATD cases in Germany during the years studied. AATD patients had a higher prevalence of arterial hypertension, chronic kidney disease and diabetes relative to non-AATD asthma or emphysema patients. When compared to non-AATD COPD patients, AATD patients had significantly more consultations and more frequent and longer hospitalisations.Our data strengthen the assumption that AATD is associated with a variety of other diseases. Healthcare utilisation appears to be higher among AATD patients as compared to patients with non-AATD-related obstructive lung diseases.

Autophagy in Hepatocytes in Infants With Alpha-1 ATD and Different Liver Disease Outcomes: A Retrospective Analysis.

OBJECTIVES: It is unclear whether a distinct activity of pathways removing the antitrypsin (AT) protein in Alpha-1-Antitrypsin Deficiency (α1ATD) are associated with an unfavorable predisposition to liver disease in the future. The aim of this study was to determine whether liverspecific activity of AT protein disposal occurs at infancy in α1ATD with PiZZ phenotype (ATZ). METHODS: Liver samples of 17 infants with unfavorable ATZ outcome (Group I, n = 8, median age  = 0.35 year) and good outcome (Group II, n = 9, 0.17 year), and 9 with biliary atresia (BA, median age = 0.17 year) as control, were enrolled. For each subject were investigated autophagy activity by mRNA, protein expression (Calnexin, Beclin-1, p62, and Parkin), and hepatocyte ultrastructure with morphometric analyses. RESULTS: No significant differences in gene expression in the liver of infants were found between the 2 ATZ groups. Although a correlation between patients' age and protein expression was observed, the ATZ groups differed Parkin immunohistochemical expression. Moreover, the hepatocytes in ATZ infants with unfavorable outcome were characterized by low Parkin expression and the presence of isolated mitophagosoms and numerous enlarged mitochondria. The mentioned findings differed in patients with BA. CONCLUSIONS: Thus, mentioned specific features occurring at infancy may suggest association with poor liver outcome. Parkin low expression could have a potential for disease prognosis and treatment; however, further studies in a greater number of patients are needed.

A New SERPINA-1 Missense Mutation Associated with Alpha-1 Antitrypsin Deficiency and Bronchiectasis.

Alpha-1-antitrypsin deficiency (AATD) is a genetic condition caused by SERPINA1 mutations, which culminates into lower protease inhibitor activity in the serum and predisposes to emphysema. Clinical manifestations of AATD are often associated to ZZ (p.Glu342Lys) and SZ (p.Glu264Val) genotypes and less frequently to rare deficiency or null alleles in heterozygous and homozygous states. We report a case of a 52-year-old woman with bronchiectasis without other potential causes other than an electrophoresis that showed a decrease of alpha-1 globin band and AAT levels below the normal value (78 mg/dl; v.n. 90-200 mg/dl). No S or Z mutation was identified, but sequencing analysis found a novel missense variant Ile74Asn (c.221T > A) in heterozygous state on an M3 allele (Glu400Asp) in the exon 2 of the SERPINA-1gene, probably leading to a dysfunctional protein. This mutation has never been previously identified, and it is interesting to note the association with bronchiectasis in the absence of emphysema.

Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

BACKGROUND: The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure. METHODS: The RAPID study was a multicentre, double-blind, randomised, parallel-group, placebo-controlled trial of A1PI treatment in patients with α1 antitrypsin deficiency. We recruited eligible non-smokers (aged 18-65 years) in 28 international study centres in 13 countries if they had severe α1 antitrypsin deficiency (serum concentration <11 µM) with a forced expiratory volume in 1 s of 35-70% (predicted). We excluded patients if they had undergone, or were on the waiting list to undergo, lung transplantation, lobectomy, or lung volume-reduction surgery, or had selective IgA deficiency. We randomly assigned patients (1:1; done by Accovion) using a computerised pseudorandom number generator (block size of four) with centre stratification to receive A1PI intravenously 60 mg/kg per week or placebo for 24 months. All patients and study investigators (including those assessing outcomes) were unaware of treatment allocation throughout the study. Primary endpoints were CT lung density at total lung capacity (TLC) and functional residual capacity (FRC) combined, and the two separately, at 0, 3, 12, 21, and 24 months, analysed by modified intention to treat (patients needed at least one evaluable lung density measurement). This study is registered with ClinicalTrials.gov, number NCT00261833. A 2-year open-label extension study was also completed (NCT00670007). FINDINGS: Between March 1, 2006, and Nov 3, 2010, we randomly allocated 93 (52%) patients A1PI and 87 (48%) placebo, analysing 92 in the A1PI group and 85 in the placebo group. The annual rate of lung density loss at TLC and FRC combined did not differ between groups (A1PI -1·50 g/L per year [SE 0·22]; placebo -2·12 g/L per year [0·24]; difference 0·62 g/L per year [95% CI -0·02 to 1·26], p=0·06). However, the annual rate of lung density loss at TLC alone was significantly less in patients in the A1PI group (-1·45 g/L per year [SE 0·23]) than in the placebo group (-2·19 g/L per year [0·25]; difference 0·74 g/L per year [95% CI 0·06-1·42], p=0·03), but was not at FRC alone (A1PI -1·54 g/L per year [0·24]; placebo -2·02 g/L per year [0·26]; difference 0·48 g/L per year [-0·22 to 1·18], p=0·18). Treatment-emergent adverse events were similar between groups, with 1298 occurring in 92 (99%) patients in the A1PI group and 1068 occuring in 86 (99%) in the placebo group. 71 severe treatment-emergent adverse events occurred in 25 (27%) patients in the A1PI group and 58 occurred in 27 (31%) in the placebo group. One treatment-emergent adverse event leading to withdrawal from the study occurred in one patient (1%) in the A1PI group and ten occurred in four (5%) in the placebo group. One death occurred in the A1PI group (respiratory failure) and three occurred in the placebo group (sepsis, pneumonia, and metastatic breast cancer). INTERPRETATION: Measurement of lung density with CT at TLC alone provides evidence that purified A1PI augmentation slows progression of emphysema, a finding that could not be substantiated by lung density measurement at FRC alone or by the two measurements combined. These findings should prompt consideration of augmentation treatment to preserve lung parenchyma in individuals with emphysema secondary to severe α1 antitrypsin deficiency. FUNDING: CSL Behring.

Different Training-Induced Skeletal Muscle Adaptations in COPD Patients with and without Alpha-1 Antitrypsin Deficiency.

BACKGROUND: Pulmonary rehabilitation (PR) improves oxidative capacity of peripheral muscles in patients with chronic obstructive pulmonary disease (COPD). The exercise-induced oxidative skeletal muscle adaptation in COPD patients with inherited alpha-1 antitrypsin deficiency (A1ATD) has not been studied. OBJECTIVES: To compare PR effects on skeletal muscle adaptation in COPD patients with and without A1ATD. METHODS: Nine COPD patients with A1ATD (genotype PiZZ, 6 receiving A1AT augmentation therapy), and 10 'usual' COPD patients (genotype PiMM) performed an incremental cycling test and underwent musculus vastus lateralis biopsies before and after a 3-week PR program including exercise training. RESULTS: PiZZ and PiMM patients improved peak work rate following PR (+9 ± 11 W, p < 0.05, and +18 ± 9 W, p < 0.001, between-group difference p < 0.05). PiMM patients increased fibre type I (+8.1%), reduced fibre type IIA (-2.1%) and hybrid fibre type IIA/IIX proportion (-3.9%). Following PR, PiMM patients also raised mitochondrial signalling proteins PGC-1α (4.5-fold), and TFAM (6.4-fold). PiZZ patients had no change in fibre type I but showed a shift of type IIA/IIX (-8.8%) towards fibre type IIA distribution (+8.9%). The capillary to fibre ratio increased by 28% (p < 0.05) in PiZZ, whereas no change was observed in PiMM patients. Linear regression analysis revealed that diffusion capacity and A1AT therapy are predictor variables for myofibre type I response to PR (r2 = 0.684, p < 0.01). CONCLUSIONS: Following a 3-week PR with comparable training modalities, PiMM but not PiZZ patients increased the oxidative myofibre type I proportion. This skeletal muscle adaptation pattern suggests better improvement of exercise capacity in PiMM than in PiZZ patients with COPD.

Adult liver disorders caused by inborn errors of metabolism: review and update.

Inborn errors of metabolism (IEMs) are a group of genetic diseases that have protean clinical manifestations and can involve several organ systems. The age of onset is highly variable but IEMs afflict mostly the pediatric population. However, in the past decades, the advancement in management and new therapeutic approaches have led to the improvement in IEM patient care. As a result, many patients with IEMs are surviving into adulthood and developing their own set of complications. In addition, some IEMs will present in adulthood. It is important for internists to have the knowledge and be familiar with these conditions because it is predicted that more and more adult patients with IEMs will need continuity of care in the near future. The review will focus on Wilson disease, alpha-1 antitrypsin deficiency, citrin deficiency, and HFE-associated hemochromatosis which are typically found in the adult population. Clinical manifestations and pathophysiology, particularly those that relate to hepatic disease as well as diagnosis and management will be discussed in detail.

Quality of Life and Its Determinants in a Multicenter Cohort of Children with Alagille Syndrome.

OBJECTIVES: To assess health-related quality of life (HRQOL) in children with Alagille syndrome (ALGS) in comparison with healthy and other liver disease cohorts, and to identify determinants of HRQOL in patients with ALGS. STUDY DESIGN: Within the Childhood Liver Disease Research Network prospective study of cholestasis, Pediatric Quality of Life Inventory (PedsQL) questionnaires were administered to 70 children with ALGS, 95 children with alpha-1-antitrypsin deficiency (A1ATD), and 49 children with other causes of chronic intrahepatic cholestasis (IHC) aged 5-18 years. Parent proxy PedsQL scores were recorded for children aged 2-18 years (98 ALGS, 123 A1ATD, and 68 IHC). RESULTS: Mean ages and total bilirubin (mg/dL) were ALGS 9.4 years; 4.4, A1ATD 9.5 years; 0.7, and IHC 10.3 years; 2.9. ALGS child PedsQL scores were lower than in healthy children and children with A1ATD (mean 73 vs 83; P = .001). Children with ALGS and IHC were similar, except in physical scores (73 vs 79; P = .05). Parents of children with ALGS perceived their children to have worse HRQOL than A1ATD (P ≤ .001) and marginally lower compared with IHC. Univariate analysis revealed ALGS child-reported scores were positively associated with better growth and inversely with total bilirubin. Growth failure, elevated international normalized ratio, and an intracardiac defect were predictive of poor parental scores (P ≤ .05). In multivariate analysis, only weight z-score remained significant for child- and parent-reported scores. CONCLUSIONS: HRQOL is impaired in children with ALGS compared with healthy and children with A1ATD, similar to children with IHC and is associated with growth failure, which is a potentially treatable cause of impaired HRQOL.

Treatment of Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease that creates multiple unique phenotypes of chronic obstructive pulmonary disease. While bronchospasm, cough, dyspnea, and sputum production all occur with AATD, the phenotypic differences require a computed tomographic (CT) scan to decipher. The availability of augmentation therapy in the United States since 1989 has generated both controversy and evidence that informs the science of usual chronic obstructive pulmonary disease (COPD). Because of the predominance of emphysema in AATD, much of the best evidence concerning biomarkers of emphysema progression comes from this population. Imaging measurement of emphysema progression, impact of emphysema phenotypes on hyperinflation and dynamic hyperinflation, and correlation with traditional spirometric measures of COPD progression are required to understand the impact of AAT therapies. These studies are important for better understanding of usual COPD pathogenesis. Significantly, there are no adequately powered research studies to determine if augmentation therapy is helpful for the non-emphysema phenotypes of AATD. Specifically, phenotypes of chronic bronchitis, asthma predominant disease, and bronchiectasis will require targeted research studies to define optimal therapy.

Low serum levels of alpha1 anti-trypsin (α1-AT) and risk of airflow obstruction in non-primary α1-AT-deficient patients with compensated chronic liver disease.

BACKGROUND: Alpha1 anti-trypsin (α1-AT), a serine protease inhibitor synthesized in the liver, is a major circulating antiprotease that provides defense against proteolytic damage in several tissues. Its deficiency is associated with airflow obstruction. The present study aimed to explore the role of α1-AT as a biomarker of airflow performance in chronic liver disease (CLD). MATERIAL/METHODS: Serum α1-AT levels and lung function (spirometry) were evaluated in non-primary α1-AT-deficient, alcoholic CLD patients without evident respiratory limitations. RESULTS: Thirty-four patients with airflow obstruction (n=11), airflow restriction (n=12), and normal airflow (n=11, age-matched controls) were eligible. α1-AT was decreased in the airflow obstruction group. ROC-cutoff α1-AT=24 mg/dL effectively discriminated airflow obstruction (AUC=0.687) and was associated with a 10-fold higher risk (p=0.0007). CONCLUSIONS: Lower α1-AT increased the risk of airflow obstruction in CLD patients without primary α1-AT deficiency.

Sex differences in alpha-1-antitrypsin deficiency lung disease-analysis from the German registry.

Alpha-1-antitrypsin deficiency (AATD) is a rare condition with clinical manifestations of the lung and the liver. There is evidence that the gender affects the clinical presentation of non-AATD chronic obstructive lung disease (COPD). The aim of this study was to analyze gender-dependent disease pattern in AATD-based COPD. Data from 1066 individuals from the German AATD registry were analyzed by descriptive and analytical statistics. The AAT genotypes comprised 820 individuals with PiZZ (male 56%, female 45%), 109 with PI SZ (male 55%; female 45%), and others (n = 137). A subgroup of 422 patients with available post-bronchodilator FEV1% predicted was analyzed in detail after stratification in spirometric GOLD stages I-IV. The age of the registered individuals is 52.2 ± 13.4 years (male: 51.91 ± 13.86 years; female: 52.76 ± 13.39 years). Female patients with GOLD I-IV showed lower numbers of pack-years and lower BMI. The time between the first symptom and the establishment of the correct diagnosis was significantly longer in female (14.47 ± 16.46 years) as compared to male individuals (12.39 ± - 14.38 years, p = 0.04). In conclusion, the data of the registry allow to characterize the natural course of the disease and highlight differences in the clinical presentation of patients with AATD-dependent COPD.

Lung Function and CT Densitometry in Subjects with alpha-1-Antitrypsin Deficiency and Healthy Controls at 35 Years of Age.

Alpha-1-antitrypsin (AAT) deficiency is a genetic risk factor for pulmonary emphysema. In 1972-74 all 200,000 Swedish new-born infants were screened for AAT deficiency. The aim of the present study was to investigate whether the PiZZ and PiSZ individuals identified by this screening have signs of emphysema and the role of smoking in this, compared with a random sample of control subjects at 35 years of age. The study participants underwent complete pulmonary function tests (PFT) and CT densitometry. The fifteenth percentile density (PD15) and the relative area below -910 HU (RA-910) were analyzed. Fifty-four PiZZ, 21 PiSZ and 66 PiMM control subjects participated in the study. No significant differences were found in lung function between the never-smoking AAT-deficient and control subjects. The 16 PiZZ ever-smokers had significantly lower carbon monoxide transfer coefficient (KCO) than the 20 PiSZ never-smokers (p = 0.014) and the 44 PiMM never-smokers (p = 0.005). After correction for the CT derived lung volume, the PiZZ ever-smokers had significantly lower PD15 (p = 0.046) than the ever-smoking controls. We conclude that 35-year-old PiZZ and PiSZ never-smokers have normal lung function when compared with never-smoking control subjects. The differences in KCO and CT densitometric parameters between the PiZZ ever-smokers and the control subjects may indicate early signs of emphysema.