Serum Levels Of Alpha-1 Antitrypsin Research Articles

Lung and liver transplantation in patients with alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) augmentation is effective in slowing the progression of emphysema due to AAT deficiency (AATD) but cannot prevent eventual progression to end-stage lung disease and complete respiratory failure, which is the leading cause of death for individuals with severe AATD. When patients develop end-stage lung disease, lung transplantation is the only treatment option available, and this can improve lung physiology and patient health status. The available data suggest that survival rates for lung transplantation are significantly higher for patients with AATD-related chronic obstructive pulmonary disease (COPD) compared with non-AATD-related COPD, but, conversely, there is a higher risk of common post-lung transplant complications in patients with AATD versus non-AATD COPD. Nevertheless, lung transplantation (single and bilateral) is favorable for patients with AATD. After respiratory failure, the second leading cause of death in patients with AATD is liver disease, for example, cirrhosis and hepatocellular carcinoma, caused by the accumulation of mutant forms of AAT retained within the liver. As with lung disease, the only treatment option for end-stage liver disease is liver transplantation. Survival rates for patients with AATD undergoing liver transplantation are also favorable, and patients, particularly pediatric patients, have benefitted from advancements in peri-/post-surgical care. As the majority of AAT is produced by the liver, the AAT phenotype of the recipient becomes that of the donor, meaning that AAT serum levels should be normalized (if the donor is AAT-replete), halting further lung and liver disease progression. However, post-liver transplant respiratory function may continue to decline in line with normal age-related lung function decline. In the most severe cases, where patients have simultaneous end-stage lung and liver disease, combined lung and liver transplantation is a treatment option with favorable outcomes. However, there is very little information available on this procedure in patients with AATD.

Alpha-1 antitrypsin deficiency is significantly associated with atopy in asthmatic patients

Background: Although the etiology and disease mechanisms of asthma and alpha-1 antitrypsin deficiency (AATD) are distinct, several reports indicate that asthma is common in AATD patients, however the relationships between asthma and AATD are poorly described in the literature. Objectives: The aim of the study was to investigate in a cohort of outpatients affected by mild to moderate asthma the clinical features that may differentiate asthmatic patients with and without mutation on SERPINA1 gene. Methods: Seven hundred thirty-five asthmatic outpatients underwent quantitative analysis of the serum level of alpha-1antitrypsin. According to the literature only sixty-seven out of seven hundred thirty-five asthmatic patients were submitted to genetic analysis to identify AATD and non-AATD subjects. Fifty-eight patients were studied. Clinical and functional data, including lung function, atopy and bronchial hyperactivity, were recorded. Results: The fifty-eight asthmatic patients were divided in AATD patients (n = 22) and non AATD patients (n = 36), according to genotype. The presence of atopy was significantly higher in patients with AATD than in those without AATD (91% vs. 64%; p = 0.031). AATD patients reported allergic manifestations more than non AATD patients (77% vs. 47%; p = 0.030). Conclusion: Our study shows that the presence of atopy in asthmatic patients with AATD is significantly higher than in asthmatic patients without gene mutation. In addition, a higher percentage of AATD patients self-reported allergic manifestations. No significant differences in respiratory symptoms, physical examination, disease severity or inflammation markers were found between AATD patients and non AATD patients.

Gene therapy for alpha 1-antitrypsin deficiency with an oxidant-resistant human alpha 1-antitrypsin.

Alpha 1-antitrypsin (AAT) deficiency, a hereditary disorder characterized by low serum levels of functional AAT, is associated with early development of panacinar emphysema. AAT inhibits serine proteases, including neutrophil elastase, protecting the lung from proteolytic destruction. Cigarette smoke, pollution, and inflammatory cell–mediated oxidation of methionine (M) 351 and 358 inactivates AAT, limiting lung protection. In vitro studies using amino acid substitutions demonstrated that replacing M351 with valine (V) and M358 with leucine (L) on a normal M1 alanine (A) 213 background provided maximum antiprotease protection despite oxidant stress. We hypothesized that a onetime administration of a serotype 8 adeno-associated virus (AAV8) gene transfer vector coding for the oxidation-resistant variant AAT (A213/V351/L358; 8/AVL) would maintain antiprotease activity under oxidant stress compared with normal AAT (A213/M351/M358; 8/AMM). 8/AVL was administered via intravenous (IV) and intrapleural (IPL) routes to C57BL/6 mice. High, dose-dependent AAT levels were found in the serum and lung epithelial lining fluid (ELF) of mice administered 8/AVL or 8/AMM by IV or IPL. 8/AVL serum and ELF retained serine protease–inhibitory activity despite oxidant stress while 8/AMM function was abolished. 8/AVL represents a second-generation gene therapy for AAT deficiency providing effective antiprotease protection even with oxidant stress.

Human-Derived α1-Antitrypsin is Still Efficacious in Heavily Pretreated Patients with Steroid-Resistant Gastrointestinal Graft-versus-Host Disease.

Almost one-half of patients developing graft-versus-host disease (GVHD) will not respond to standard first-line steroid treatment. Alpha-1 antitrypsin (AAT) is able to induce tolerance in preclinical models of GVHD. AAT alters the cytokine milieu, promotes a tolerogenic shift of dendritic cells, and skews effector T cells toward regulatory T cells. Gastrointestinal steroid-refractory (SR)-GVHD is a protein-losing enteropathy that might represent the optimal setting in which to use AAT. Here we analyze the outcomes of 16 patients treated with human-derived AAT in advanced-stage gut SR-GVHD, with two-thirds of the patients having failed at least 1 treatment for SR-GVHD. The overall response rate (ORR) was 44%, with a complete response (CR) rate of 27%. Gastrointestinal response was observed in 61% of patients. The median time to best response was 21 days (range, 6 to 26 days). At day 56 after AAT treatment, all CRs were maintained, and the ORR was 39%. The 1-year overall survival was 48% (95% confidence interval, 26% to 74%). Ancillary studies showed that AAT serum levels were in the normal range at the beginning of treatment, whereas fecal loss was elevated. AAT levels consistently rose after exogenous administration, but no correlation was found between serum levels and response. REG3α and IL-33 levels were associated with response while, in contrast to previous reports, regulatory T cells decreased during AAT treatment. This retrospective analysis supports a previous report of AAT as a promising agent in the management of gut SR-GVHD and should prompt its evaluation at an earlier stage.

Molecular diagnosis of alpha1-antitrypsin deficiency: A new method based on Luminex technology.

BackgroundAlpha1‐antitrypsin deficiency (AATD) is an under‐diagnosed hereditary disorder characterized by reduced serum levels of alpha1‐antitrypsin (AAT) and increased risk to develop lung and liver diseases at an early age. AAT is encoded by the highly polymorphic SERPINA1 gene. The most common deficiency alleles are S and Z, but more than 150 rare variants lead to low levels of the protein. To identify these pathological allelic variants, sequencing is required. Since traditional sequencing is expensive and time‐consuming, we evaluated the accuracy of A1AT Genotyping Test, a new diagnostic genotyping kit which allows to simultaneously identify and genotype 14 deficiency variants of the SERPINA1 gene based on Luminex technology.MethodsA total of 418 consecutive samples with AATD suspicion and submitted to the Italian Reference laboratory between January and April 2016 were analyzed both by applying the diagnostic algorithm currently in use, and by applying A1AT Genotyping Test.ResultsThe assay gave the following results: 101 samples (24.2%) were positive for at least one of the 14 deficiency variants, 316 (75.6%) were negative for all the variants analyzed. The identified mutations showed a 100% correlation with the results obtained with our diagnostic algorithm. Seventeen samples (4%) resulted negative for the assay but sequencing identified other rare pathological variants in SERPINA1 gene.ConclusionThe A1AT Genotyping Test assay was highly reliable and robust and allowed shorter diagnostic times. In few cases, it has been necessary to sequence the SERPINA1 gene to identify other rare mutations not included in the kit.

Serum Levels of Alpha1-antitrypsin and Their Relationship With COPD in the General Spanish Population

BackgroundLow plasma level of alpha1-antitrypsin (AAT) is an established risk factor for early-onset chronic obstructive lung disease (COPD). However, less attention is given to the levels of AAT in the general population. MethodsThis is a part of a multicentre, population-based study conducted at 11 sites throughout Spain. Plasma levels of AAT were available for 837 persons with a mean (SD) age of 58.05 (11.3) years: 328-smokers, 272-ex-smokers and 237 non-smokers. Out of 837, 303 (36.2%) had a diagnosis of COPD, 222 (26.5%) had respiratory symptoms but no COPD, and 312 (37.3%) were healthy controls. ResultsIn the whole cohort, the mean level of plasma AAT was 1.51 (0.47)g/L. Levels were higher in COPD patients [1.55 (0.45)g/L] and individuals with respiratory symptoms [1.57 (0.47)g/L] than in controls [1.43 (0.47)g/L], p<0.001, a finding which persisted after correction for age and CRP. Plasma AAT levels were negatively associated with FEV1/FVC ratio, after adjustment for age, sex, smoking status, CRP, TNFα, fibrinogen and albumin. The risk for COPD was significantly associated with higher AAT levels in univariate and multivariate models, with odds ratios of 1.8 and 1.5, respectively. In the univariate and multivariate models smoking status, gender, and CRP levels were also associated with COPD probability, demonstrating that they act independently. ConclusionIncreased circulating levels of AAT, similarly to CRP and other markers of systemic inflammation, is an important feature of COPD. Our results highlight a complex interrelationship between levels of AAT and health of respiratory system.

Serum Alpha-1 Antitrypsin Levels and the Clinical Course of Chronic Obstructive Pulmonary Disease.

PurposeAlpha-1 antitrypsin deficiency is associated with the development of chronic obstructive pulmonary disease (COPD), whereas increased levels of serum alpha-1antitrypsin occur in response to inflammation. The effects of alpha-1 antitrypsin levels on the clinical course of COPD had been unclear. We investigated the association of serum alpha-1 antitrypsin levels with the clinical course of COPD patients based on data from a 10-year prospective cohort study.Patients and methodsWe analyzed 278 COPD patients who participated in the Hokkaido COPD cohort study and who did not meet the criteria for alpha-1 antitrypsin deficiency. We divided the subjects into 3 groups according to quartiles of serum alpha-1 antitrypsin levels at baseline: lower group (<116 mg/dL, n = 66); middle group (116 to ≤141 mg/dL, n = 145); and higher group (>141 mg/dL, n = 67). The annual change in forced expiratory volume in 1 s (FEV1) and events of COPD exacerbation were monitored during the first 5 years, and mortality was followed-up during the entire 10 years.ResultsAt baseline, the higher group showed lower body mass index; higher computed tomography emphysema score; lower diffusing capacity; higher levels of acute-phase proteins; and higher blood neutrophil counts. Longitudinal analyses revealed that in the higher group, the annual decline in FEV1 was rapid and the 10-year mortality was higher, but there was no association between serum alpha-1 antitrypsin levels and time to first exacerbation.ConclusionCOPD subjects with higher serum alpha-1 antitrypsin levels were associated with a worse systemic inflammation status and higher 10-year mortality.

2381 Abnormal Aminotransferases, Think Beyond the Liver

INTRODUCTION: Liver aminotransferases are frequently utilized to evaluate liver and biliary tract diseases. Elevated aminotransferases are non-specific and further testing is usually necessary to identify the underlying cause. We present a puzzling case of abnormal aminotransferases. CASE DESCRIPTION/METHODS: A 28-year-old male patient was referred to hepatology clinic for evaluation of abnormal laboratory findings. Routine blood tests revealed elevated AST of 67 U/L and ALT of 77 U/L. Alkaline phosphatase was 36 U/L and total bilirubin, total protein, and albumin were within normal limits. Review of systems was unremarkable. Past medical and surgical histories were insignificant. His only home medication was diphenhydramine. Family history was negative for liver disease or malignancies. He reported drinking 5-6 drinks per week and denied the use of tobacco or illicit drugs. On physical exam, body mass index (BMI) was 28. Abdomen was soft, non-tender, and slightly distended. He had normal bowel sounds and no organomegaly. Abdominal ultrasound showed a normal liver and gallbladder. Hepatitis A, hepatitis B, and hepatitis C serology were unremarkable. Serum ceruloplasmin and alpha-1 antitrypsin levels were normal. Antinuclear antibody (ANA) and antimitochondrial antibodies were negative. Anti-smooth muscle antibody (ASMA) was borderline positive with a titer of 1:20. Ferritin level was 100 and transferrin saturation (TSAT) was elevated at 59%. Subsequently, a liver biopsy was performed and revealed normal liver architecture with intact hepatic lobules. Additional history revealed that the patient gets leg cramps while walking and could not run as fast as the other kids in school. Upper musculoskeletal exam was unremarkable. However, lower musculoskeletal exam revealed a 4/5 weakness in addition to bulky calf muscles. Laboratory workup showed elevated CK of 1002 U/L and aldolase of 11.2 U/L. The patient was referred to rheumatology and neurology for further evaluation of myopathy. DISCUSSION: The evaluation of elevated aminotransferases can be challenging especially in asymptomatic patients. In our patient, extensive liver work-up came back normal. Although he had elevated BMI, there was no evidence of non-alcoholic steatohepatitis (NASH). Muscle disorders/myopathies may present with elevated aminotransferases. A good history and physical exam can provide important clues to reach the correct diagnosis.

Is there any association between rs1303 (Pi*M3) variant of alpha-1 antitrypsin gene and atrial septal aneurysm development?

Atrial septal aneurysm (ASA) is one of the congenital heart defects. The underlying pathophysiology of ASA has not been fully understood yet. Alpha-1 antitrypsin (A1AT) is a serine protease inhibitor glycoprotein, which is held responsible from tissue wall proteolysis if it is deficient in the body. The aim of this study was to investigate A1AT serum levels and the rs1303 (Pi*M3) variant in A1AT gene in patients with ASA. Thirty patients (7 male and 23 female) with isolated ASA and 33 patients (11 male and 22 female) with normal atrial septum on echocardiography were included in this study. A1AT serum levels of study patients were measured quantitatively by the enzyme-linked immune sorbent assay (ELISA) method. The A1AT gene mutation rs1303 was analyzed by genotyping, which is performed on genomic DNA extracted from circulating mononuclear blood cells. Single-nucleotide polymorphism was evaluated on polymerase chain reaction using commercial kits. A1AT serum levels were not statistically different among patients with and without ASA (9.52 ± 4.33 µg/mL vs 9.83 ± 5.27 µg/mL, respectively, P = .80). A1AT homozygote mutation (PiM3M3) was significantly higher in the ASA group than the control group (21 vs 11, OR (95% CI): 6.68 [2.09-21.40], P = .001). A1AT serum levels were similar among patients with normal A1AT allele (PiMM), homozygote variant (PiM3M3), and heterozygote variant (PiMM3) (P = .79). This preliminary study revealed that homozygote A1AT rs1303 (PiM3M3) variant is significantly higher in patients with isolated ASA and may be associated with ASA development. Large scale comprehensive studies are needed to validate these results.

Serum Levels of Alpha1-antitrypsin and Their Relationship With COPD in the General Spanish Population

BackgroundLow plasma level of alpha1-antitrypsin (AAT) is an established risk factor for early-onset chronic obstructive lung disease (COPD). However, less attention is given to the levels of AAT in the general population. MethodsThis is a part of a multicentre, population-based study conducted at 11 sites throughout Spain. Plasma levels of AAT were available for 837 persons with a mean (SD) age of 58.05 (11.3) years: 328-smokers, 272-ex-smokers and 237 non-smokers. Out of 837, 303 (36.2%) had a diagnosis of COPD, 222 (26.5%) had respiratory symptoms but no COPD, and 312 (37.3%) were healthy controls. ResultsIn the whole cohort, the mean level of plasma AAT was 1.51 (0.47)g/L. Levels were higher in COPD patients [1.55 (0.45)g/L] and individuals with respiratory symptoms [1.57 (0.47)g/L] than in controls [1.43 (0.47)g/L], p<0.001, a finding which persisted after correction for age and CRP. Plasma AAT levels were negatively associated with FEV1/FVC ratio, after adjustment for age, sex, smoking status, CRP, TNFα, fibrinogen and albumin. The risk for COPD was significantly associated with higher AAT levels in univariate and multivariate models, with odds ratios of 1.8 and 1.5, respectively. In the univariate and multivariate models smoking status, gender, and CRP levels were also associated with COPD probability, demonstrating that they act independently. ConclusionIncreased circulating levels of AAT, similarly to CRP and other markers of systemic inflammation, is an important feature of COPD. Our results highlight a complex interrelationship between levels of AAT and health of respiratory system.

Beyond the lungs: Alpha-1 antitrypsin's potential role in human gestation.

Alpha-1 antitrypsin (AAT) is an acute-phase protein with strong inhibitory activity towards proteolytic enzymes, mainly elastase but also trypsin, chymotrypsin and thrombin. The biological role of the protein and the effects of its deficiency have been subjects of scientific research for years, yet in many areas our knowledge remains incomplete. Alpha-1 antitrypsin deficiency (AATD), a defect in AAT synthesis and functionality, is one of the most frequently inherited genetic disorders among Caucasian populations. Its severe form is characterized by very low serum levels of AAT, and it most often affects the lungs (causing early-onset emphysema or chronic obstructive lung disease (COPD)) and/or liver (leading to jaundice and liver cirrhosis in children and adults). However, little is known about other possible clinical consequences of AAT deficiency. We discuss AAT's potential role in mechanisms regulating human fertility and gestation, with a particular emphasis on the clinical context and on indications for AATD diagnostic testing.

Bridging from Intramuscular to Limb Perfusion Delivery of rAAV: Optimization in a Non-human Primate Study

Phase 1 and phase 2 gene therapy trials using intramuscular (IM) administration of a recombinant adeno-associated virus serotype 1 (rAAV1) for replacement of serum alpha-1 antitrypsin (AAT) deficiency have shown long-term (5-year) stable transgene expression at approximately 2% to 3% of therapeutic levels, arguing for the long-term viability of this approach to gene replacement of secreted serum protein deficiencies. However, achieving these levels required 100 IM injections to deliver 135 mL of vector, and further dose escalation is limited by the scalability of direct IM injection. To further advance the dose escalation, we sought to bridge the rAAV-AAT clinical development program to regional limb perfusion, comparing two methods previously established for gene therapy, peripheral venous limb perfusion (VLP) and an intra-arterial push and dwell (IAPD) using rAAV1 and rAAV8 in a non-human primate (rhesus macaque) study. The rhesus AAT transgene was used with a c-myc tag to enable quantification of transgene expression. 5 cohorts of animals were treated with rAAV1-IM, rAAV1-VLP, rAAV1-IAPD, rAAV8-VLP, and rAAV8-IAPD (n = 2–3), with a dose of 6 × 1012 vg/kg. All methods were well tolerated clinically. Potency, as determined by serum levels of AAT, of rAAV1 by the VLP method was twice that observed with direct IM injection; 90 μg/mL with VLP versus 38 μg/mL with direct IM injection. There was an approximately 25-fold advantage in estimated vector genomes retained within the muscle tissue with VLP and a 5-fold improvement in the ratio of total vector genomes retained within muscle as compared with liver. The other methods were intermediate in the potency and retention of vector genomes. Examination of muscle enzyme (CK) levels indicated rAAV1-VLP to be equally safe as compared with IM injection, while the IAPD method showed significant CK elevation. Overall, rAAV1-VLP demonstrates higher potency per vector genome injected and a greater total vector retention within the muscle, as compared to IM injection, while enabling a much greater total dose to be delivered, with equivalent safety. These data provide the basis for continuation of the dose escalation of the rAAV1-AAT program in patients and bode well for rAAV-VLP as a platform for replacement of secreted proteins.

Detection of alpha-1 antitrypsin gene mutations by polymerase chain reaction in patients with chronic obstructive pulmonary disease

Introduction. The alpha-1 antitrypsin deficiency is the best described genetic cause of chronic obstructive pulmonary disease. The study of the alpha-1 antitrypsin deficiency, as the most important genetic risk factor for chronic obstructive pulmonary disease, is an important step in developing a strategy for the prevention and treatment of this disease. The aim of the study was detection of homozygous and heterozygous deficient gene alleles (protease inhibitor Z and protease inhibitor S) for alpha-1 antitrypsin in the group of patients with chronic obstructive pulmonary disease with the predominance of lung emphysema, as well as determination of a positive correlation between the serum levels of alpha-1 antitrypsin and the corresponding alpha-1 antitrypsin genotype. Material and Methods. The study included 90 patients, mutually unrelated individuals, hospitalized due to lung emphysema. The control group included 10 subjects, with no clinical signs of lung emphysema, but with a family history of chronic obstructive pulmonary disease. We attempted to identify the most common deficient alleles (protease inhibitor Z and protease inhibitor S) and the concentration of alpha-1 antitrypsin in the serum of the examinees. The polymorphism between the two allelic forms, protease inhibitor Z and protease inhibitor S, was detected by real-time polymerase chain reaction. Results. Protease inhibitor MM genotype alpha-1 antitrypsin was present in all 90 patients with the diagnosis of pulmonary emphysema, and the serum levels of alpha-1 antitrypsin were within the range of reference values. In the control group, there were two cases with mutated protease inhibitor MZ genotype, and in these 2 subjects the serum level of alpha-1 antitrypsin was at the lower limit of reference values. Conclusion. In patients diagnosed with lung emphysema, protease inhibitor MM genotype of alpha-1 antitrypsin and normal serum alpha-1 antitrypsin levels, the genetically- determined deficiency of alpha-1 antitrypsin is not responsible for the development of chronic obstructive pulmonary disease.

Comparative evaluation of serum alpha-1antitrypsin levels in patients with oral squamous cell carcinoma and in subjects with tobacco habit without carcinoma.

Aim/Objectives:To evaluate serum levels of Alpha-1 antitrypsin in patients with oral squamous cell carcinoma and compare them with that of healthy subjects with and without tobacco habits.Materials and Method:The sample of 83 subjects was divided into three groups: 30 subjects with oral squamous cell carcinoma formed Group A. The age, sex, habit matched 23 healthy subjects with tobacco habit formed Group B and 30 healthy without history of consumption of tobacco formed Group C. Analysis of the samples was done using Alpha 1 antitrypsin kit and spectrophotometer.Results:There was a 2.33-fold rise in serum levels of Alpha 1 antitrypsin in Group A compared to Group B, 3.71-fold rise in Group A compared to Group C and 1.59-fold rise in Group B compared to Group C (P < 0.001). A definite rise in serum Alpha 1 antitrypsin levels in patients with oral squamous cell carcinoma as compared with healthy subjects with and without tobacco habits was observed.Conclusion:Alpha1-antitrypsin can be used as an adjunct to various diagnostic procedures implied for the evaluation of oral squamous cell carcinoma.

SERPINA1 Hepatocyte-Specific Promoter Polymorphism Associate with Chronic Obstructive Pulmonary Disease in a Study of Kashmiri Ancestry Individuals

Different mutations in coding and non-coding sequences of the SERPINA1 gene have been implicated in the pathogenesis of COPD. However, - 10T/Cmutation in the hepatocyte-directed promoter region has not been associated with COPD pathogenesis so far. Here, we report an increased frequency of - 10C genotype that is associated with decreased levels of serum alpha1-antitrypsin (α1AT) in COPD patients. The quantification of serum α1AT was done by ELISA, the phenol-chloroform method was used for DNA extraction, PCR products were directly sequenced. The IBM SPSS Statistics v21 software was used for statistical analyses of the data. The mean serum α1AT level was found to be 1.203+0.239 and 3.162+0.160 g/L in COPD cases and in control, respectively. The - 10C allele is associated with an increased risk of COPD [OR, 3.50 (95%CI, 1.86-6.58); p < 0.001]. The combined variant genotype (TT+CC) was significantly found associated with an increased risk of COPD [OR, 3.20 (95% CI, 1.47-6.96); p = 0.003]. A significant association of the family history with COPD (overall p value= 0.0331) suggests that genetics may play an important role in the pathogenesis of COPD. The polymorphism associated with hepatocyte-specific promoter region (- 10T/C) is likely to be associated withthe pathogenesis of COPD. It is quite possible that the change of the base in thehepatocyte-specific promoterof the SERPINA1 gene can modulate its strength, thereby driving the reduced expression of α1AT.

Disturbed Inflammatory/Anti-inflammatory Milieu and Activation of Primary Phase Reactants may Underlie Development and Recurrence of First trimester Pregnancy Loss.

Objective: Estimation of serum levels of tumor necrosis factor-a (TNF-a), interleukin (IL-) 6 and 10 and alpha-1 antitrypsin (AAT) in pregnant women with current pregnancy loss (CPL) and non-pregnant women with history of recurrent PL (RPL) compared versus women with normal pregnancy (NP).Patients & Methods: All studied women underwent clinical and vaginal ultrasonographic examination for assurance of inclusion criteria and then gave blood samples for ELISA estimation of studied parameters.Results: Patients of CPL and RPL groups showed significantly high serum TNF-a and IL-6 levels with significantly lower serum IL-10 levels than women of NP group with significant difference between CPL and RPL groups. Serum AAT levels were significantly lower in CPL group than RPL and NP groups with significantly lower levels in RPL than NP group. High serum TNF-a and low AAT levels showed high positive predictive value (PPV) and sensitivity, respectively, for possibility of presence or recurrence of PLConclusion: Disturbed serum levels of pro- and anti-inflammatory cytokines could diagnose CPL with high PPV and persistence of their disturbed levels may predispose to RPL. Activation of primary phase reactant system may underlie, accompany or initiate PL, so low serum AAT during 1st trimester and its persistently low serum levels during inter-pregnancy intervals could be used as screening test for presence or liability for development of PL.

Alpha-2 Macroglobulin Serum Level in Patients with Alpha-1 Antitrypsin Deficiency

Background and objectives Alpha-2 Macroglobulin (A2M) is a plasma protein with proteolytic effects on many proteases. In patients with an inborn alpha-1 antitrypsin deficiency (AATD) the homeostasis between proteases and antiproteases is disturbed. The aim of this study was to compare the levels of AAT and A2 M in patients and controls. We hypothesized that in patients with AATD A2 M levels are elevated. Methods Patients with AATD (polymorphism Pi*ZZ, Pi*SZ, Pi*MZ and rare gene variants) as well as healthy volunteers (Pi*MM) were tested for A2 M and AAT levels. The concentration of the proteins was measured by nephelometry. The polymorphisms Pi*Z and Pi*S were detected by polymerase chain reaction (PCR), the rare genetic variants were identified by sequencing. Results In our study, a total of 291 individuals were included. It could be shown that a significant increase in A2 M levels in the serum could be observed in the presence of a gene polymorphism (Pi*ZZ) and an alpha-1 antitrypsin serum level < 50 mg/dl compared to the healthy volunteers. Conclusions In this study, an inverse correlation between the serum levels of AAT and A2 M was found in the presence of a gene polymorphism (Pi*ZZ). Further studies are necessary to elucidate the clinical significance of increased A2 M serum levels in patients with severe AAT deficiency Pi*ZZ and rare gene variants whose AAT serum level is < 50 mg/dl.

Alpha-1 Antitrypsin Deficiency: Current Perspective from Genetics to Diagnosis and Therapeutic Approaches.

Alpha-1 antitrypsin (A1AT) is a 52-kDa, acute phase glycoprotein encoded by the protease inhibitor (PI) locus, located on the long arm of chromosome 14 (14q31-32.3). Its structure is composed of a total of 7 exons, 4 coding (II, III, IV, and V) and 3 non-coding (IA, IB, and IC). A1AT is produced primarily by hepatocytes and acts as a serine protease inhibitor with antiprotease and immunoregulatory activities. The main target of A1AT is neutrophil elastase (NE), an enzyme released during a neutrophil-mediated inflammatory process. When the enzyme is not adequately balanced by A1AT activity, it can cause tissue injury and destruction. A1AT deficiency (A1ATD) is a genetic autosomal recessive disease, characterized by low serum levels of A1AT. The condition may lead to liver disease, early-onset pulmonary emphysema and, rare multi-organ vasculitis, necrotizing panniculitis and fibromyalgia. At least 100 allelic variants of the polymorphic PI locus have been described with groups including associations with different A1AT plasma levels and functions. Treatments with purified A1AT preparations, obtained through pooled human plasma (augmentation therapy), have been proven to improve survival and disease-related quality of life, as well as, slow down the progression of organ damage. Furthermore, ongoing research is now focusing on the development of specifically targeted, new medications. The aim of this review is to summarize our knowledge of the genetic A1AT variants, focusing on their variable clinical manifestation, report routine and recently updated laboratory diagnostic techniques, and to highlight the relevance of early diagnosis of A1ATD. Moreover, we will review the role of augmentation therapy recommendations and future perspectives focusing on a personalized treatment of A1ATD.

P2.01-079 The Serum Levels of Alpha-1 Antitrypsin Are Strongly Associated with Its Local Production by Tumor Cells in NSCLC Patients

P2.01-079 The Serum Levels of Alpha-1 Antitrypsin Are Strongly Associated with Its Local Production by Tumor Cells in NSCLC Patients

Pathophysiology of Alpha-1 Antitrypsin Lung Disease.

Alpha-1 antitrypsin deficiency (AATD) is an inherited disorder characterized by low serum levels of alpha-1 antitrypsin (AAT). Loss of AAT disrupts the protease-antiprotease balance in the lungs, allowing proteases, specifically neutrophil elastase, to act uninhibited and destroy lung matrix and alveolar structures. Destruction of these lung structures classically leads to an increased risk of developing emphysema and chronic obstructive pulmonary disease (COPD), especially in individuals with a smoking history. It is estimated that 3.4 million people worldwide have AATD. However, AATD is considered to be significantly underdiagnosed and underrecognized by clinicians. Contributing factors to the diagnostic delay of approximately 5.6years are: inadequate awareness by healthcare providers, failure to implement recommendations from the American Thoracic Society/European Respiratory Society, and the belief that AATD testing is not warranted. Diagnosis can be attained using qualitative or quantitative laboratory testing. The only FDA approved treatment for AATD is augmentation therapy, although classically symptoms have been treated similarly to those of COPD. Future goals of AATD treatment are to use gene therapy using vector systems to produce therapeutic levels of AAT in the lungs without causing a systemic inflammatory response.