Serum AAT Levels Research Articles

Alpha-1-antitrypsin deficiency: increasing awareness and improving diagnosis.

Alpha-1-antitrypsin deficiency (AATD) is a hereditary disorder that is characterized by a low serum level of alpha-1-antitrypsin (AAT). The loss of anti-inflammatory and antiproteolytic functions, together with pro-inflammatory effects of polymerized AAT contribute to protein degradation and increased inflammation resulting in an increased risk of developing chronic obstructive pulmonary disease (COPD) and emphysema, especially in smokers. AATD is a rare disease that is significantly underdiagnosed. According to recent data that are based on extrapolations, in many countries only 5-15% of homozygous individuals have been identified. Furthermore, the diagnostic delay typically exceeds 5 years, resulting in an average age at diagnosis of about 45 years. Although the American Thoracic Society/European Respiratory Society recommendations state that all symptomatic adults with persistent airway obstruction should be screened, these recommendations are not being followed. Potential reasons for that include missing knowledge about the disease and the appropriate tests, and the low awareness of physicians with regard to the disorder. Once the decision to initiate testing has been made, a screening test (AAT serum level or other) should be performed. Further diagnostic evaluation is based on the following techniques: polymerase chain reaction (PCR) for frequent and clinically important mutations, isoelectric focusing (IEF) with or without immunoblotting, and sequencing of the gene locus coding for AAT. Various diagnostic algorithms have been published for AATD detection (severe deficiency or carrier status). Modern laboratory approaches like the use of serum separator cards, a lateral flow assay to detect the Z-protein, and a broader availability of next-generation sequencing are recent advances, likely to alter existing algorithms.

SERPINA1 Full-Gene Sequencing Identifies Rare Mutations Not Detected in Targeted Mutation Analysis

Genetic α-1 antitrypsin (AAT) deficiency is characterized by low serum AAT levels and the identification of causal mutations or an abnormal protein. It needs to be distinguished from deficiency because of nongenetic causes, and diagnostic delay may contribute to worse patient outcome. Current routine clinical testing assesses for only the most common mutations. We wanted to determine the proportion of unexplained cases of AAT deficiency that harbor causal mutations not identified through current standard allele-specific genotyping and isoelectric focusing (IEF). All prospective cases from December 1, 2013, to October 1, 2014, with a low serum AAT level not explained by allele-specific genotyping and IEF were assessed through full-gene sequencing with a direct sequencing method for pathogenic mutations. We reviewed the results using American Council of Medical Genetics criteria. Of 3523 cases, 42 (1.2%) met study inclusion criteria. Pathogenic or likely pathogenic mutations not identified through clinical testing were detected through full-gene sequencing in 16 (38%) of the 42 cases. Rare mutations not detected with current allele-specific testing and IEF underlie a substantial proportion of genetic AAT deficiency. Full-gene sequencing, therefore, has the ability to improve accuracy in the diagnosis of AAT deficiency.

Identification and characterisation of eight novel SERPINA1 Null mutations.

BackgroundAlpha-1 antitrypsin (AAT) is the most abundant circulating antiprotease and is a member of the serine protease inhibitor (SERPIN) superfamily. The gene encoding AAT is the highly polymorphic SERPINA1 gene, found at 14q32.1. Mutations in the SERPINA1 gene can lead to AAT deficiency (AATD) which is associated with a substantially increased risk of lung and liver disease. The most common pathogenic AAT variant is Z (Glu342Lys) which causes AAT to misfold and polymerise within hepatocytes and other AAT-producing cells. A group of rare mutations causing AATD, termed Null or Q0, are characterised by a complete absence of AAT in the plasma. While ultra rare, these mutations confer a particularly high risk of emphysema.MethodsWe performed the determination of AAT serum levels by a rate immune nephelometric method or by immune turbidimetry. The phenotype was determined by isoelectric focusing analysis on agarose gel with specific immunological detection. DNA was isolated from whole peripheral blood or dried blood spot (DBS) samples using a commercial extraction kit. The new mutations were identified by sequencing all coding exons (II-V) of the SERPINA1 gene.ResultsWe have found eight previously unidentified SERPINA1 Null mutations, named: Q0cork, Q0perugia, Q0brescia, Q0torino, Q0cosenza, Q0pordenone, Q0lampedusa, and Q0dublin . Analysis of clinical characteristics revealed evidence of the recurrence of lung symptoms (dyspnoea, cough) and lung diseases (emphysema, asthma, chronic bronchitis) in M/Null subjects, over 45 years-old, irrespective of smoking.ConclusionsWe have added eight more mutations to the list of SERPINA1 Null alleles. This study underlines that the laboratory diagnosis of AATD is not just a matter of degree, because the precise determination of the deficiency and Null alleles carried by an AATD individual may help to evaluate the risk for the lung disease.Electronic supplementary materialThe online version of this article (doi:10.1186/s13023-014-0172-y) contains supplementary material, which is available to authorized users.

Peripheral blood hematopoietic stem and progenitor cell frequency is unchanged in patients with alpha-1-antitrypsin deficiency.

Granulocyte-colony-stimulating factor (G-CSF)-induced hematopoietic stem and progenitor cell (HSPC) mobilization is associated with the release of neutrophil-derived proteases. Previously, we have shown that alpha-1-antitrypsin (AAT) inhibits these proteases in mice, resulting in inhibition of HSPC mobilization. Here, we studied the relationship between AAT and HSPC in steady state and cytokine-induced mobilization in humans. Patients with alpha-1-antitrypsin deficiency (AATD) have an 85-90 % decrease of AAT in the peripheral blood (PB). We hypothesized that this leads to increased proteolytic activity in the bone marrow and increased steady-state PB HSPC numbers. Using flow cytometry and semi-solid cell culture, we found no significant difference in PB HSPC in AATD patients (n = 18) as compared to controls (n = 22). Healthy stem cell donors (n = 43) were mobilized with G-CSF for 5 days and the number of CD45(+)/CD34(+) HSPC were determined in PB. We found that, during mobilization, PB AAT levels increased significantly, positively correlating with PB CD45(+)/CD34(+) cells (r = 0.31, p = 0.005). In conclusion, although serum AAT levels and HSPC mobilization in healthy stem cell donors are positively correlated, AAT is not an indispensable protease-inhibitor in the constitutive circulation of HSPC. These findings suggest a model in which both protease-dependent and -independent pathways contribute to HSPC mobilization.

Are Serum Alpha-1-Antitrypsin and Alpha-2-Macroglobulin Levels Related with Tumor Histology or Stage of the Lung Cancer?.

In certain types of cancer, increased serum protease inhibitor levels were identified and clues showing that, serum levels of protease inhibitor could be used in the assessment of prognosis and dissemination of tumor were obtained. We aimed to reveal whether serum alpha-1-antitrypsin (AAT) and alpha-2-macroglobulin (AMG) levels of patients with lung cancer are related with histological type, clinical stage, and advance of cancer. The patients enrolled in the study were the ones with a histopathologic diagnosis of primary lung cancer and they were not administered any treatment before. Levels of serum AAT and AMG were analyzed at the moment of diagnosis. A total of 47 patients were enrolled in the study – 42 males and 5 females. The average age was 58.9. Tumor cell type was non-small cell lung carcinoma (NSCLC) in 36 and small cell lung carcinoma in 11 patients. There was a negative correlation between serum AAT level and age (p= 0.21 r=-0.339). No correlation was identified between serum AMG level and age (p= 0.138 r= 0.222). There was no significant relation between histological types of lung cancer and serums AAT and AMG (p= 0.807, p= 0.411 respectively). AAT and AMG levels were not different in limited and extensive small cell lung carcinoma (p= 0.201 and p= 0.465). AAT and AMG levels based on stages were not found to be different in NSCLC (p= 0.646 and p=0.650). AAT and AMG levels did not vary based on distant metastasis or local spread in NSCLC (p= 0.371 and p= 0.676). Serum alpha-1-antitrypsin and alpha-2-macroglobulin levels in patients with lung cancer do not vary based on histological types, stage of the disease, local, distant and lymphatic spread of the tumor.

GPs Meet Rare Lung Disorders Task Force factsheet: -1 antitrypsin deficiency

<h3>Definition</h3> α-1 antitrypsin deficiency (AATD) is a genetic disorder that manifests as pulmonary emphysema, liver cirrhosis and, rarely, as the skin disease panniculitis, or as vasculitis and is characterised by low serum levels of AAT, the main protease inhibitor in human serum. <h3>Key messages</h3> Think about AATD if your patient had emphysema at younger age. Assess the levels of blood AAT to ascertain the diagnosis by the finding of reduced levels. Refer the patient to a Department with experience in lung/liver manifestations of AATD. Follow the patient longitudinally in collaboration with the reference center. Issues to consider are replacement therapy (if needed or available) and clinical evolution toward respiratory or liver failure.

Outcomes for recipients of liver transplantation for alpha-1-antitrypsin deficiency-related cirrhosis

Alpha-1-antitrypsin (AAT) deficiency is a rare genetic disease caused by an abnormal production of the serine protease inhibitor AAT. Liver transplantation (LT) cures cirrhosis caused by AAT deficiency and restores the normal production of AAT. There are few reports on the post-LT outcomes of patients with AAT deficiency. The aim of this study was to determine the characteristics and outcomes of patients undergoing LT for AAT deficiency at 3 large transplant centers. All patients undergoing LT at these 3 transplant centers from 1987 to 2012 for AAT deficiency (ZZ or SZ phenotype) were included. The most recent 50 patients with the MZ phenotype were also included for comparison. Data were collected retrospectively from internal databases and medical records. Seventy-three patients (50 with the ZZ phenotype and 23 with the SZ phenotype)underwent LT. The mean age was 52.8 years, and the majority of the patients (75.6%) were men. Before LT, serum AAT levels were lower for the ZZ patients versus the SZ patients (28.3 versus 58.0 mg/dL, P < 0.001). More than 40% of the SZ patients had an additional liver disease, whereas 8% in the ZZ group and 90% in the MZ group did. Before LT, there was no significant difference in pulmonary function between the ZZ and SZ groups. Seventeen patients (all with ZZ phenotype)had pulmonary function tests performed before and after LT. The forced expiratory volume in 1 second (FEV1) continued to decline for the majority. The 1-, 3-, 5-, and 10-year post-LT survival rates were 86%, 83%, 80%, and 72%, respectively, for the ZZ patients and 91%, 86%, 79%, and 79%, respectively, for the SZ patients. In conclusion, survival after LT for patients with ZZ or SZ AAT deficiency is excellent. Despite the normalization of AAT levels after LT, FEV1 continues to decline unexpectedly after LT in some ZZ and SZ patients.

Causal and Synthetic Associations of Variants in the SERPINA Gene Cluster with Alpha1-antitrypsin Serum Levels

Several infrequent genetic polymorphisms in the SERPINA1 gene are known to substantially reduce concentration of alpha1-antitrypsin (AAT) in the blood. Since low AAT serum levels fail to protect pulmonary tissue from enzymatic degradation, these polymorphisms also increase the risk for early onset chronic obstructive pulmonary disease (COPD). The role of more common SERPINA1 single nucleotide polymorphisms (SNPs) in respiratory health remains poorly understood.We present here an agnostic investigation of genetic determinants of circulating AAT levels in a general population sample by performing a genome-wide association study (GWAS) in 1392 individuals of the SAPALDIA cohort.Five common SNPs, defined by showing minor allele frequencies (MAFs) >5%, reached genome-wide significance, all located in the SERPINA gene cluster at 14q32.13. The top-ranking genotyped SNP rs4905179 was associated with an estimated effect of β = −0.068 g/L per minor allele (P = 1.20*10−12). But denser SERPINA1 locus genotyping in 5569 participants with subsequent stepwise conditional analysis, as well as exon-sequencing in a subsample (N = 410), suggested that AAT serum level is causally determined at this locus by rare (MAF<1%) and low-frequent (MAF 1–5%) variants only, in particular by the well-documented protein inhibitor S and Z (PI S, PI Z) variants. Replication of the association of rs4905179 with AAT serum levels in the Copenhagen City Heart Study (N = 8273) was successful (P<0.0001), as was the replication of its synthetic nature (the effect disappeared after adjusting for PI S and Z, P = 0.57). Extending the analysis to lung function revealed a more complex situation. Only in individuals with severely compromised pulmonary health (N = 397), associations of common SNPs at this locus with lung function were driven by rarer PI S or Z variants. Overall, our meta-analysis of lung function in ever-smokers does not support a functional role of common SNPs in the SERPINA gene cluster in the general population.

PTU-116 Transplantation for ALD: Lessons from the Explant

IntroductionAlcoholic liver disease (ALD) remains one of the commonest indications for liver transplantation in Europe. The histological features of ALD vary, depending on extent and stage of injury, No features...

Comparison of fructosamine and alpha-1-antitrypsin in patients with diabetic retinopathy

The role of alpha-1-antitrypsin (A1AT), serine protease inhibitor, in diabetic retinopathy is not exactly defined yet. The major pathogenic factor of diabetic microangiopathy is the non-enzymatic protein glycosylation. Chronically elevated serum glucose levels can disturb the structure and function of vascular matrix proteins by cross-linking rearrangement and cause narrowing of the luminal diameter of the micro vessels in the retina, i. e. diabetic retinopathy. Fructosamine test is considered clinically useful for assessing the short-term integrated blood glucose control in the previous one to three weeks. It is based on the alkaline reducing activity of non-enzymatic glycated serum proteins as selected according to their biological half-lives and relative concentrations, e.g. albumin, IgA, apolipoproteins, haptoglobin, transferrin, alpha-2-macroglobulin and A1AT. The aim of this study was to estimate the comparison between the serum fructosamine levels and A1AT in diabetic retinopathy patients. It covered 18 patients aged between 38 and 66 years and hospitalized in the Department of Internal Diseases, Medical University of Pleven, and 20 healthy subjects. Examinations of A1AT were done after the method of rocket immunoelectrophoresis. Fructosamine was measured after Johnson colorimetric method (Roche test fructosamine). Serum A1AT levels were significantly decreased in 11 patients (61.1%) and increased in 6 ones (33.3%) as there was no difference in one patient (5.5%) when compared to the control group. Serum fructosamine levels were significantly increased in 10 patients (55.5%) and reduced in two ones (11.1%) as there was no difference between these levels and the reference ones in 5 patients (27.7%). The statistical analysis showed a significant correlation (p &lt; 0.005) between the elevated serum fructosamine levels and the decreased A1AT ones in diabetic retinopathy patients. The non-enzymatic protein glycosylation manifested by the elevated fructosamine level corresponds with the increased proteolytic activity of the enzymes, i.e. A1AT deficiency as a pathogenic factor for the development of diabetic retinopathy. Scripta Scientifica Medica 2012; 44(2): 45-48.

Serum levels and genotype distribution of α1-antitrypsin in the general population

Rationaleα1-Antitrypsin (AAT) deficiency is one of the commonest rare respiratory disorders worldwide. Diagnosis, assessment of risk for developing chronic obstructive pulmonary disease (COPD), and management of replacement therapy require the...

Sanger sequencing solved a cryptic case of severe alpha1-antitrypsin deficiency

Alpha(1)-antitrypsin deficiency (AATD) is a clinically under-diagnosed genetic disorder that originates from deleterious mutations in the alpha(1)-antitrypsin (AAT) gene, SERPINA1. Severe deficiency is associated with significant pulmonary and hepatic malfunctions. Conventional clinical diagnosis involves the evaluation of serum AAT level and detection of diseased protein isoforms. In this communication, we describe the investigations of a case of severe AATD in which the AAT levels were well below those expected from the MZ phenotype determined by isoelectric focusing for protease inhibitor type (IEF PI-typing). In addition to the traditional diagnostic method that combines the assessment of serum AAT concentration and IEF PI-typing, we investigated the SERPINA1 gene of the proband and participating family members for mutations using Sanger sequencing. We identified a novel mutation (M409T) in the proband, initially missed by the standard diagnostic approach. The novel mutation was present in 4 out of 8 family members who participated in the study. This report illustrates the diagnostic value of incorporating exon sequencing of the AAT gene into the algorithm for evaluating AATD, particularly when the AAT serum level is significantly lower than expected from IEF PI-typing.

The effects of weekly augmentation therapy in patients with PiZZ &amp;alpha;1-antitrypsin deficiency

BackgroundThe major concept behind augmentation therapy with human α1-antitrypsin (AAT) is to raise the levels of AAT in patients with protease inhibitor phenotype ZZ (Glu342Lys)-inherited AAT deficiency and to protect lung tissues from proteolysis and progression of emphysema.ObjectiveTo evaluate the short-term effects of augmentation therapy (Prolastin®) on plasma levels of AAT, C-reactive protein, and chemokines/cytokines.Materials and methodsSerum and exhaled breath condensate were collected from individuals with protease inhibitor phenotype ZZ AAT deficiency-related emphysema (n = 12) on the first, third, and seventh day after the infusion of intravenous Prolastin. Concentrations of total and polymeric AAT, interleukin-8 (IL-8), monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, vascular endothelial growth factor, and C-reactive protein were determined. Blood neutrophils and primary epithelial cells were also exposed to Prolastin (1 mg/mL).ResultsThere were significant fluctuations in serum (but not in exhaled breath condensate) levels of AAT polymers, IL-8, monocyte chemotactic protein-1, IL-6, tumor necrosis factor-α, and vascular endothelial growth factor within a week of augmentation therapy. In general, augmented individuals had higher AAT and lower serum levels of IL-8 than nonaugmented subjects. Prolastin added for 3 hours to neutrophils from protease inhibitor phenotype ZZ individuals in vitro reduced IL-8 release but showed no effect on cytokine/chemokine release from human bronchial epithelial cells.ConclusionWithin a week, augmentation with Prolastin induced fluctuations in serum levels of AAT polymers and cytokine/chemokines but specifically lowered IL-8 levels. It remains to be determined whether these effects are related to the Prolastin preparation per se or to the therapeutic efficacy of augmentation with AAT.

Does Augmentation with Alpha1-Antitrypsin Affect Neutrophil Extracellular Traps Formation?

Alpha1-Antitrypsin (AAT) is a major circulating inhibitor of neutrophil proteases, specifically elastase that has broad substrate specificity and can degrade many connective tissue matrix constituents. Severe inherited Z (Glu342Lys) deficiency of AAT (AATD) is characterized by a low serum AAT level (less than 20% of normal which is 11μM/L), the protease/antiprotease balance shift in favor of the elastase and an increased risk of early onset pulmonary emphysema. This lends support to the protease-antiprotease imbalance theory of the pathogenesis of emphysema and to AAT augmentation therapy.

A Review of α1-Antitrypsin Deficiency

α(1)-Antitrypsin (AAT) deficiency is an underrecognized genetic condition that affects approximately 1 in 2,000 to 1 in 5,000 individuals and predisposes to liver disease and early-onset emphysema. AAT is mainly produced in the liver and functions to protect the lung against proteolytic damage (e.g., from neutrophil elastase). Among the approximately 120 variant alleles described to date, the Z allele is most commonly responsible for severe deficiency and disease. Z-type AAT molecules polymerize within the hepatocyte, precluding secretion into the blood and causing low serum AAT levels (∼ 3-7 μM with normal serum levels of 20-53 μM). A serum AAT level of 11 μM represents the protective threshold value below which the risk of emphysema is believed to increase. In addition to the usual treatments for emphysema, infusion of purified AAT from pooled human plasma-so-called "augmentation therapy"-represents a specific therapy for AAT deficiency and raises serum levels above the protective threshold. Although definitive evidence from randomized controlled trials of augmentation therapy is lacking and therapy is expensive, the available evidence suggests that this approach is safe and can slow the decline of lung function and emphysema progression. Promising novel therapies are under active investigation.

Population Genetic Screening for Alpha1-Antitrypsin Deficiency in a High-Prevalence Area

Background: Current guidelines for α1-antitrypsin deficiency (AATD) state that adult population screening should only be done in high-risk areas. Up-to-date genetic methods are always recommended. Objectives: To determine the prevalence of AATD in a suspected high-risk area by population screening, applying new genetic analyses and comparing the prevalence of liver and lung abnormalities in subjects with or without AATD. Methods: Adult residents of Pezzaze, a village in an Italian alpine valley, voluntarily participated in the screening, and were examined for: nephelometric α1-antitrypsin (AAT) serum level, DNA analysis (mutagenic polymerase chain reaction and restriction fragment length polymorphism tests for Z and S AATD causative mutations, and denaturing high-performance liquid chromatography and/or direct gene sequencing if needed), serum aspartate and alanine transaminases, a respiratory questionnaire and the Medical Research Council dyspnea index scale. The prevalence of AATD was compared with that expected in Italy (Hardy-Weinberg equilibrium), and transaminases and the prevalence of respiratory symptoms were compared between study groups. Results: Of 1,353 residents, 817 (60.4%) participated; 67 (8.2%) had low AAT serum levels (<90 mg/dl); 118 were carriers of AATD-associated alleles, 4 (0.5%) homozygotes or compound heterozygotes (1 Z, 1 S, 2 ZP_brescia), 114 (14%) heterozygotes (46 Z, 52 S, 9 P_brescia, 4 M_wurzburg, 2 I, 1 P_lowell). The prevalence and frequency of all AATD-related alleles was higher than expected for Italy (p < 0.001). There were no differences in symptoms of respiratory disease and transaminases between individuals with normal and low serum AAT. Conclusion: The screening design is one of the main strengths of this study. The large number of mostly asymptomatic individuals with AATD identified suggests that in high-risk areas adult population screening programs employing the latest genetic methods are feasible. Early recognition of individuals at risk means primary or secondary prevention measures can be taken.

Diagnóstico tardío de déficit de &amp;alpha;-1-antitripsina

Alpha-1 antitrypsin deficiency (AAT-D) is a genetic disease, relatively common in populations of European ancestry. AAT-D remains undiagnosed in many patients, and there are often long delays between the onset of respiratory symptoms and diagnosis. AAT-D can be readily diagnosed by measurement of the serum or plasma protein level, which should be confirmed by assessing the genotype or protein phenotype when AAT levels are below the normal range. Close monitoring for the development or progression of lung disease or liver disease is required, and can improve the prognosis. We show the case of a 69 year old woman with recurrent respiratory infections and asthma symptoms. The serum levels of AAT were below the normal range, and ZZ genotype was confirmed. The delayed diagnosis of our patient seems to emphasize the need to remind the doctors about AAT-D, frequently associated with asthma or COPD symptoms.

Alpha-1 antitrypsin deficiency related liver disease: Is it worth a search in India?

Alpha-1-antitrypsin deficiency (AATD) is the commonest genetic cause of liver disease in children from the West and also a major cause of emphysema and chronic obstructive pulmonary disease in adults. The mechanism of lung and liver injury are distinct and unique. The liver disease appears to involve a “gain of function” mechanism in which the retained mutant AAT molecule in the endoplasmic reticulum triggers a series of events which lead to programmed hepatocyte death, inflammation, fibrosis and cirrhosis. More than 100 mutant alleles have been identified, but only few are associated with liver disease. The commonest deficiency phenotypes are PIZZ, PISS and PISZ. Other rare alleles account for 5% of PI variants and include Mmalton and MDuarte among others(1). In this issue of the Journal, Arora, et al.(2) have evaluated 1250 children (840 chronic liver disease [CLD], 410 neonatal cholestasis [NC]) and 450 controls for AATD. Authors carried out investi-gations of screening and phenotyping (PI) with isoelectric focussing (IEF) in all the subjects (n=1700). On screening 7.8% (98/1700) subjects were shown to be deficient (low serum AAT level or absent/faint alpha-1 globulin band on serum agarose electrophoresis or PAS positive diastase resistant globules on liver histology). Phenotyping was normal (MM) in 99.8% (n=1697) children and the other 3 subjects had other variants (MIE, MP, MC: one each), none of which are known to be associated with liver disease. Fifty subjects (CLD 34, NC 16) of the 98 screen positive were subjected to genotype sequencing; none had PIZ or PIS genotypes. However two children had a novel mutation at position 333 in exon V; both having cryptogenic CLD, low serum AAT levels and positive globules on liver biopsy on immune histochemistry, all pointing towards a diagnosis of AATD. The study suggests that the commonest AAT deficiency alleles of PIZ and PIS as described in the West are not seen in Indian children. Thus AATD is a rare cause of liver diseases in India.

Accelerated Spirometric Decline in New York City Firefighters With α;1-Antitrypsin Deficiency

On September 11, 2001, the World Trade Center (WTC) collapse caused massive air pollution, producing variable amounts of lung function reduction in the New York City Fire Department (FDNY) rescue workforce. α₁-Antitrypsin (AAT) deficiency is a risk factor for obstructive airway disease. This prospective, longitudinal cohort study of the first 4 years post-September 11, 2001, investigated the influence of AAT deficiency on adjusted longitudinal spirometric change (FEV₁) in 90 FDNY rescue workers with WTC exposure. Workers with protease inhibitor (Pi) Z heterozygosity were considered moderately AAT deficient. PiS homozygosity or PiS heterozygosity without concomitant PiZ heterozygosity was considered mild deficiency, and PiM homozygosity was considered normal. Alternately, workers had low AAT levels if serum AAT was ≤ 20 μmol/L. In addition to normal aging-related decline (37 mL/y), significant FEV(1) decline accelerations developed with increasing AAT deficiency severity (110 mL/y for moderate and 32 mL/y for mild) or with low AAT serum levels (49 mL/y). Spirometric rates pre-September 11, 2001, did not show accelerations with AAT deficiency. Among workers with low AAT levels, cough persisted in a significant number of participants at 4 years post-September 11, 2001. FDNY rescue workers with AAT deficiency had significant spirometric decline accelerations and persistent airway symptoms during the first 4 years after WTC exposure, representing a novel gene-by-environment interaction. Clinically meaningful decline acceleration occurred even with the mild serum AAT level reductions associated with PiS heterozygosity (without concomitant PiZ heterozygosity).

Alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder associated with the development of liver and lung disease. AAT is a 52-kD glycoprotein, produced mainly by hepatocytes and secreted into the blood. Agglomeration of the AAT-protein in hepatocytes can result in liver disease. Exposure to smoke is the major risk factor for the development of lung disease characterised as early chronic obstructive lung disease (COPD). Diagnosis is based on the analysis of the AAT genotype and phenotype. The measurement of the AAT serum level is useful as screening test. Liver biopsy is not necessary to establish the diagnosis. Therapy for AAT-related liver disease is supportive, a specific therapy is not available. AATD is a rare condition (1:5000-10000) and, as a consequence, data and information on diagnosis and treatment are not easily accessible. This chapter provides a comprehensive overview on AATD, covering basic biology, diagnostic and therapeutic approaches.