Low Alpha-1 Antitrypsin Levels Research Articles

Alpha-1 antitrypsin deficiency hidden in allegedly normal variants

Introduction Rare variants of Alpha-1 antitrypsin (AAT) deficiency (AATD) have been described by the Spanish registry of patients with AATD. The great majority of these rare variants are Mmalton alleles and many recent case series of them have been identified in the Canary Islands. The objective of this study was to analyze the distribution of Mmalton mutations in a Canarian population previously studied for the most common deficient alleles, namely PI*S (S) and PI*Z (Z), with PI*M (M) being the normal variant. Methods A cross-sectional study of 648 patients with allergic asthma was carried out. Mmalton mutation of the SERPINA1 gene was assayed by real-time PCR. Results Of the 648 patients, 3 (0.46%) were carriers of a Mmalton allele. All of them had low levels of AAT (53.9 mg/dL, 90 mg/dL, and 61 mg/dL, respectively) and were asymptomatic, showing normal lung function, radiological images, and levels of hepatic transaminases. Conclusion In conclusion, although the most frequent AATD genotypes are Z and S alleles, it is important to consider other rare variants, particularly when low AAT serum levels are observed. Although individuals with the Mmalton mutation usually have a heterogenous clinical presentation and very low levels of AAT, all the patients in this study were asymptomatic.

Correlation of Low Levels of α-1 Antitrypsin and Elevation of Neutrophil to Lymphocyte Ratio with Higher Mortality in Severe COVID-19 Patients.

Background Variations in COVID-19 prevalence, severity, and mortality rate remain ambiguous. Genetic or individual differences in immune response may be an explanation. Moreover, hyperinflammation and dysregulated immune response are involved in the etiology of severe forms of COVID-19. Therefore, the aim of the present study was to analyze serum alpha-1 antitrypsin (AAT) levels, as an acute-phase plasma protein with immunomodulatory effect and neutrophil to lymphocyte ratio (NLR) as a marker of inflammation response in severe COVID-19 illness. Methods In this retrospective observational cohort study, 64 polymerase chain reaction (PCR) positive COVID-19 hospitalized patients were studied for AAT, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), troponin, complete blood count (CBC), random blood sugar, serum glutamate oxaloacetate transaminase (SGOT), serum glutamate pyruvate transaminase (SGPT), and arterial oxygen saturation (O2sat) at admission and during hospitalization. Results The results showed that hospitalized patients with COVID-19 had low serum levels of AAT and high CRP levels at the first days of hospitalization. In particular, the percentages of individuals with low, normal, and high AAT levels were 7.80%, 82.80%, and 9.40%, respectively, while high and low values of CRP accounted for 86.70% and 13.30% of patients. Most of the patients had an upward neutrophil to lymphocyte ratio (NLR) trend, with a higher mortality rate (p < 0.05) and troponin levels (p < 0.05). However, comorbidities, CRP alterations, ESR alterations, nonfasting blood sugar, SGOT, SGPT, O2sat, RBC, and PLT values were not significantly different between the NLR downward and upward trend groups. Conclusions The current study revealed that severe COVID-19 patients had low serum AAT levels related to CRP values. Therefore, AAT response may be considered as a new mechanism by which some COVID-19 patients show immune dysregulation and more severe symptoms.

Future Therapeutic Options for Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder that results in low circulating levels of alpha-1 antitrypsin (AAT). Low levels of AAT can result in damaged lung tissue, and pro-inflammatory state. The accumulation of polymerized Z-AAT protein within hepatocytes also causes cytotoxicity, resulting in liver cirrhosis. The current therapy includes weekly augmentation with plasma derived products. This has not proven to affect the progression of liver disease. Current research is targeting new modalities of treatment that will improve the progression of liver toxicity related to the polymerization of the Alpha-1 protein in the hepatocytes, in addition to offering patients more flexible treatment options, including oral therapy and less frequent intravenous infusions. These novel therapies include recombinant protein therapy, small molecule correctors, inhaled AAT therapy, RNA interference and monoclonal antibodies. The anti-inflammatory effect of Alpha-1 therapy is being explored in other disease states, including COVID-19 Pneumonia.

Serum Levels of Glutamate-Pyruvate Transaminase, Glutamate-Oxaloacetate Transaminase and Gamma-Glutamyl Transferase in 1494 Patients with Various Genotypes for the Alpha-1 Antitrypsin Gene

Background: Patients with liver disease associated with alpha-1 antitrypsin deficiency (AATD) are homozygous for the Z mutation, leading to chronic liver damage. Objective: To assess the serum levels of glutamate-oxaloacetate transaminase (GOT), glutamate-pyruvate transaminase (GPT), and gamma-glutamyl transpeptidase (GGT) in patients with different genotypes for the alpha-1 antitrypsin (AAT) gene. Methods: Patients (n = 1494) underwent genotyping of the SERPINA1 gene, together with a determination of AAT and GOT and GPT and GGT transaminase levels. Patients with a deficient allele (n = 476) and with a normal genotype were compared. Results: A statistically significant association was found between deficient genotypes and GOT (p < 0.0003), GPT (p < 0.002), and GGT (p < 0.006). Comparing GOT levels in patients with PI*Z deficient variant versus those with normal genotype, an odds ratio (OR) of 2.72 (CI: 1.5–4.87) (p < 0.0005) was obtained. This finding was replicated with the PI*Z allele and the GPT values (OR = 2.31; CI: 1.45–3.67; p < 0.0003). In addition, a statistically significant association was found between liver enzymes and AAT values. Conclusion: The PI*Z allele seemed to be a risk factor for the development of liver damage. AAT deficient genotypes were associated with GOT, GPT, and GGT altered values. Low AAT levels were associated with high GPT and GGT levels.

Monocytes and Macrophages in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is a genetic condition characterised by low circulating levels of alpha-1 antitrypsin (AAT), a serine proteinase inhibitor. The most common deficiency variants are the S and Z mutations, which cause the accumulation of misfolded AAT in hepatocytes resulting in endoplasmic reticular stress and insufficient release of AAT into the circulation (<11μmol/L). This leads to liver disease, as well as an increased risk of emphysema due to unopposed proteolytic activity of neutrophil-derived serine proteinases in the lungs. AATD has been traditionally viewed as an inflammatory disorder caused directly by a proteinase-antiproteinase imbalance in the lung, but increasing evidence suggests that low AAT levels may affect other cellular functions. Recently, AAT polymers have been identified in both monocytes and macrophages from AATD patients and evidence is building that these cells may also play a role in the development of AATD lung disease. Alveolar macrophages are phagocytic cells that are important in the lung immune response but are also implicated in driving inflammation. This review explores the potential implications of monocyte and macrophage involvement in non-liver AAT synthesis and the pathophysiology of AATD lung disease.

Research progress of hepatocyte transplantation treatment for alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency is an autosomal codominant genetic disease characterized by low levels of alpha-1 antitrypsin in the blood. Clinically, in young patients, it mainly manifests as emphysema, acute/chronic liver injury and liver cancer. The treatment methods include symptomatic treatment and alpha -1 antitrypsin supplementation. However, the existing treatment cannot prevent the liver fibrosis progression. At present, more than ten cases of the disease have been reported in China, but the understanding of this disease is still indecisive. Moreover, there exists no biotherapy drug for this disorder. This article introduces the research progress of hepatocyte transplantation treatment for this disorder.

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.

Neutrophil Modulation in Alpha-1 Antitrypsin Deficiency.

Neutrophils have been implicated in the pathogenesis of alpha-1 antitrypsin deficiency (AATD) since the first descriptions of the disease. Neutrophil proteinases can cause all lung manifestations of AATD, from small airways destruction, to emphysema, to chronic bronchitis and airflow obstruction. Initially, it was proposed that neutrophil functions were normal in AATD, responding in an initially physiological manner to a high burden of pulmonary inflammation. More recent studies have shed new light on this, describing changes in neutrophil responses (a modulation of usual cellular functions) in the presence of inflammation or infection which might enhance tissue damage while impeding bacterial clearance, providing some evidence to support there being an AATD neutrophil phenotype. Many facets of neutrophil function in AATD can be explained by the loss of alpha-1 antitrypsin (AAT) in diverse biological processes. If this were the only reason for altered neutrophil functions, one would predict similar disease presentation across affected people. However, this is not the case. Despite similar (low) levels of AAT, lung disease is extremely variable in AATD, with some patients suffering a significant burden of lung disease and some much less, irrespective of smoking habits and, in some cases, despite augmentation therapy. This review will explore how complex neutrophil responses are and how they are altered with age, inflammation and AATD. Further, it will discuss the need to understand more completely which aspects of AATD-associated disease are driven by neutrophils and how patients more susceptible to neutrophil dysfunction could be identified to potentially stratify treatment approaches.

Obez çocuklarda alkolik olmayan yağlı karaciğer hastalığı ve eşlik eden diğer karaciğer hastalıkları

Objective: The prevalence of non-alcoholic fatty liver disease (NAFLD) in children increased parallel to the increment of childhood obesity. Also, NAFLD may be the presenting feature of different liver diseases in non-obese children. We aimed to determine whether there were co-existing liver diseases in overweight and obese children with NAFLD. Material and Methods: Pediatric gastroenterology outpatient clinic records of obese and overweight patients, aged between 5-18 years, were retrospectively reviewed. Seventy patients who had liver steatosis on ultrasonography, and alanine aminotransferase (ALT) levels were higher than 1.5 times the upper limit of normal were recruited to the study. The demographic findings, laboratory tests for infectious, metabolic, and autoimmune causes, abdominal ultrasonography and liver biopsy findings of patients were recorded. Results: At presentation, 94.2% of the patients (n: 66) had mild transaminase elevation. All patients were negative for viral hepatitis, anti-tissue transglutaminase immunoglobulin (Ig) A, anti-liver-kidney-microsome type 1 and anti-smooth muscle antibody. They had normal erythrocyte sedimentation rate (ESR) , C-reactive protein (CRP), ceruloplasmin, and total IgG levels . O nly one patient with low alpha-1 antitrypsin levels had heterozygotes of the PiMZ phenotype. Three (4.3%) patients had antinuclear antibody ( ANA) positivity. 44.7% of patients were given ursodeoxycholic acid treatment. On follow-up, normalization of ALT was achieved in 31 (44.2%) patients at mean 6.1 ±4.6 (2-19) months, but no relation was found between normalization and ursodeoxycholic acid treatment. A patient with ANA positivity had increased ALT, ESR , CRP , IgG levels and ANA titers o n follow-up, and she was diagnosed with autoimmune hepatitis with the support of liver biopsy. Under prednisolone and azathioprine treatment, ESR and IgG levels were normalized, ALT and ANA titers decreased. Conclusion: Other causes of chronic hepatitis should be screened in obesity-related non-alcoholic fatty liver disease and the development of autoimmune hepatitis should be kept in mind in the presence of ANA.

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.

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-1 Antitrypsin Levels and Polymorphisms in Interstitial Lung Diseases.

Alpha-1 antitrypsin deficiency may be a potential predisposing factor for interstitial lung fibrosis. We investigated alpha-1 antitrypsin levels and its polymorphisms in patients with interstitial lung disease. A total of 103 interstitial lung disease patients were compared. The mean alpha-1 antitrypsin level in idiopathic interstitial pneumonia patients was 1.67 ± 0.33 g/L, and it was 1.54 ± 0.37 g/L in patients with nonidiopathic interstitial pneumonia (P = 0.13). Low alpha-1 antitrypsin levels were more frequently observed in nonidiopathic interstitial pneumonia patients compared with idiopathic interstitial pneumonia, but the difference was not statistically significant (8.9% vs. 0%, respectively, P = 0.4). In 100 patients, the normal PiMM genotype was detected, while abnormal ones (PiMZ, n = 2, 1.9%; PiMS, n = 1, 0.97%) were determined in three cases. When the frequency of alpha-1 antitrypsin polymorphism in interstitial lung disease patients was compared with the data of the healthy population, no significant difference was detected for the PiMZ and PiMS variants (P = 0.15 and P = 0.44, respectively). Lower levels of serum alpha-1 antitrypsin were more frequent in nonidiopathic interstitial pneumonia patients than idiopathic interstitial pneumonia without an increase in genetic polymorphism. The difference was not statistically significant.

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.

Gene Therapy for Alpha-1 Antitrypsin Deficiency Lung Disease.

Alpha-1 antitrypsin (AAT) deficiency, characterized by low plasma levels of the serine protease inhibitor AAT, is associated with emphysema secondary to insufficient protection of the lung from neutrophil proteases. Although AAT augmentation therapy with purified AAT protein is efficacious, it requires weekly to monthly intravenous infusion of AAT purified from pooled human plasma, has the risk of viral contamination and allergic reactions, and is costly. As an alternative, gene therapy offers the advantage of single administration, eliminating the burden of protein infusion, and reduced risks and costs. The focus of this review is to describe the various strategies for AAT gene therapy for the pulmonary manifestations of AAT deficiency and the state of the art in bringing AAT gene therapy to the bedside.

Alpha-1 Antitrypsin Deficiency in COPD Patients: A Cross-Sectional Study

IntroductionAlpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with early onset chronic obstructive pulmonary disease (COPD) and liver disease. It is also a highly under-diagnosed condition. As early diagnosis could prompt specific interventions such as smoking cessation, testing of family members, genetic counseling and use of replacement therapy, screening programs are needed to identify affected patients. ObjectiveTo estimate the prevalence of severe AATD in COPD patients by routine dried blood spot testing and subsequent genotyping in patients with alpha-1 antitrypsin (AAT) levels below an established threshold. Materials and methodsCross-sectional study of adult COPD patients attending the Hospital Dr. Antonio Cetrángolo (Buenos Aires, Argentina) between 2009 and 2012. The study consisted of capillary blood collection via finger stick to determine AAT levels, clinical evaluation and lung function tests. Genotype was determined in AAT-deficient patients. ResultsA total of 1002 patients were evaluated, of whom 785 (78.34%) had normal AAT levels, while low AAT levels were found in 217 (21.66%). Subsequent genotyping of the latter sub-group found: 15 (1.5%, 95% CI 0.75–2.25) patients with a genotype associated with severe AATD, of whom 12 were ZZ (1.2%, 95% CI 0.52–1.87) and 3 SZ (0.3%, 95% CI 0–0.64). The remaining 202 patients were classified as: 29 Z heterozygotes (2.89%, 95% CI 1.86–3.93), 25 S heterozygotes (2.5%, 95% CI 1.53–3.46) and 4 SS (0.4%, 95% CI 0.01–0.79). A definitive diagnosis could not be reached in 144 patients (14.37%, 95% CI 12.2–16.54). ConclusionThe strategy using an initial serum AAT level obtained by dried blood spot testing and subsequent genotyping was a satisfactory initial approach to a screening program for severe AAT, as a definitive diagnosis was achieved in 87% of patients. However, results were not obtained for logistical reasons in the remaining 13%. This major obstacle may be overcome by the use of dried blood spot phenotyping techniques. We believe this approach for detecting AATD in COPD patients, in compliance with national and international guidelines, is supported by our results.

Déficit de alfa 1 antitripsina en pacientes con EPOC: estudio de corte transversal

IntroductionAlpha-1 antitrypsin deficiency (AATD) is a genetic disorder associated with early onset chronic obstructive pulmonary disease (COPD) and liver disease. It is also a highly under-diagnosed condition. As early diagnosis could prompt specific interventions such as smoking cessation, testing of family members, genetic counselling and use of replacement therapy, screening programs are needed to identify affected patients. ObjectiveTo estimate the prevalence of severe AATD in COPD patients by routine dried blood spot testing and subsequent genotyping in patients with alpha-1 antitrypsin (AAT) levels below an established threshold. Materials and methodsCross-sectional study of adult COPD patients attending the Hospital Dr. Antonio Cetrángolo (Buenos Aires, Argentina) between 2009 and 2012. The study consisted of capillary blood collection via finger stick to determine AAT levels, clinical evaluation and lung function tests. Genotype was determined in AAT-deficient patients. ResultsA total of 1,002 patients were evaluated, of whom 785 (78.34%) had normal AAT levels, while low AAT levels were found in 217 (21.66%). Subsequent genotyping of the latter sub-group found: 15 (1.5%, 95% CI 0.75-2.25) patients with a genotype associated with severe AATD, of whom 12 were ZZ (1.2%, 95% CI 0.52-1.87) and 3 SZ (0.3%, 95% CI 0-0.64). The remaining 202 patients were classified as: 29 Z heterozygotes (2.89%, 95% CI 1.86-3.93), 25 S heterozygotes (2.5%, 95% CI 1.53-3.46) and 4 SS (0.4%, 95% CI 0.01-0.79). A definitive diagnosis could not be reached in 144 patients (14.37%, 95% CI 12.2-16.54). ConclusionThe strategy using an initial serum AAT level obtained by dried blood spot testing and subsequent genotyping was a satisfactory initial approach to a screening program for severe AAT, as a definitive diagnosis was achieved in 87% of patients. However, results were not obtained for logistical reasons in the remaining 13%. This major obstacle may be overcome by the use of dried blood spot phenotyping techniques. We believe this approach for detecting AATD in COPD patients, in compliance with national and international guidelines, is supported by our results.

Low yield and utilization of confirmatory testing in a cohort of patients with liver disease assessed for alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin (AAT) deficiency is often evaluated in patients with liver disease of unknown etiology. We aimed to describe the practice and yield of AAT testing at a large clinical laboratory. This is the retrospective cohort study of all patients with AAT measurements at one major clinical laboratory between 2003 and 2012. AAT was measured in 4,985 patients by more than 339 physicians. Eight (0.16 %) patients were found to have AAT deficiency disease. Low AAT levels were associated with two clinical factors. Aspartate aminotransferase (>40 IU/L) was inversely related, odds ratio (OR) 0.53, 95 % CI (0.32-0.88), while comorbid pulmonary disease was positively correlated, OR 4.00, 95 % CI (1.37-9.30). Non-directed testing was common. More than 90 % of patients with ALT > 40 were simultaneously assessed for AAT deficiency, hepatitis B or C, hemochromatosis, and autoimmune hepatitis. Rates of phenotype utilization were low for patients with low AAT (23, 31.5 %). Phenotype utilization was inversely related to the practice of simultaneous testing for simultaneous autoimmune hepatitis [OR 0.34 (95 % CI 0.13-0.88)], hepatitis B [OR 0.32 (95 % CI 0.11-0.89)], hepatitis C [OR 0.36 (95 % CI 0.13-1.00)], and Wilson disease evaluation [OR 0.35 (95 % CI 0.14-0.92)]. The yield of AAT testing for patients with elevated liver enzymes is low. Utilization of phenotype testing is low and related to non-directed liver testing patterns. These data suggest a role for guidelines and laboratory protocols to encourage directed testing and phenotype utilization.

Diabetic retinopathy: could the alpha-1 antitrypsin be a therapeutic option?

Diabetic retinopathy is one of the most important causes of blindness. The underlying mechanisms of this disease include inflammatory changes and remodeling processes of the extracellular-matrix (ECM) leading to pericyte and vascular endothelial cell damage that affects the retinal circulation. In turn, this causes hypoxia leading to release of vascular endothelial growth factor (VEGF) to induce the angiogenesis process. Alpha-1 antitrypsin (AAT) is the most important circulating inhibitor of serine proteases (SERPIN). Its targets include elastase, plasmin, thrombin, trypsin, chymotrypsin, proteinase 3 (PR-3) and plasminogen activator (PAI). AAT modulates the effect of protease-activated receptors (PARs) during inflammatory responses. Plasma levels of AAT can increase 4-fold during acute inflammation then is so-called acute phase protein (APPs). Individuals with low serum levels of AAT could develop disease in lung, liver and pancreas. AAT is involved in extracellular matrix remodeling and inflammation, particularly migration and chemotaxis of neutrophils. It can also suppress nitric oxide (NO) by nitric oxide sintase (NOS) inhibition. AAT binds their targets in an irreversible way resulting in product degradation. The aim of this review is to focus on the points of contact between multiple factors involved in diabetic retinopathy and AAT resembling pleiotropic effects that might be beneficial.Electronic supplementary materialThe online version of this article (doi:10.1186/0717-6287-47-58) contains supplementary material, which is available to authorized users.

154: The role of circulating alpha-1 antitrypsin in recurrent pregnancy loss

in recurrent pregnancy loss Tamar Madar, Eli C Lewis, Galit Shahaf, Guy Twina, Joel Baron, Shimrit Yaniv Salem, Moshe Mazor, Arnon Wiznitzer, Gershon Holcberg, Eyal Sheiner Soroka University Medical Center, Ben-Gurion University of the Negev, Department of Obstetrics and Gynecology, Faculty of Health Sciences, Meitar, Israel, Soroka University Medical Center, Ben-Gurion University of the Negev, Department of Clinical Biochemistry, Faculty of Health Sciences, Beer-Sheva, Israel, Soroka University Medical Center, Ben-Gurion University of the Negev, Department of Obstetrics and Gynecology, Faculty of Health Sciences, Beer-Sheva, Israel, Soroka University Medical Center, Ben-Gurion University of the Negev, Department of Obstetrics and Gynecology, Beer-Sheva, IL, Israel, Soroka University Medical Center, Ben-Gurion University of the Negev, Department of Obstetrics and Gynecology, Beer-Sheva, Israel OBJECTIVE: Alpha-1 antitrypsin (AAT) inhibits a wide variety of proteases and possesses anti-inflammatory, immune modifying and tissue-protective properties. AAT levels rise 4 to 6-fold during acute phase responses, as well as during pregnancy. Low AAT levels and activity were previously linked with several pregnancy complications. Various causes have been attributed to recurrent miscarriages, including immunologic and inflammatory factors. Therefore, the purpose of the present prospective study was to examine whether low plasma concentration and activity of AAT might correlate with recurrent pregnancy loss. STUDY DESIGN: We conducted a prospective case control study that included patients with recurrent pregnancy loss (two or more consecutive miscarriages; n 18), patients with sporadic pregnancy loss (n 16) and individuals undergoing elective termination of normal pregnancy per social considerations (n 13). Blood samples were drawn before performing dilatation and curettage and immediately transferred in cold to the analysis lab. AAT activity and concentration were determined in maternal serum samples by standard ELISA and enzymatic assays. Analyses were performed in duplicates and repeated twice for each sample in separate sessions. RESULTS: Patients with recurrent pregnancy loss as well as patients with sporadic miscarriages depicted AAT levels that were significantly lower than the control group of normal pregnancies; the levels in recurrent miscarriage was 2.39 0.33 -fold lower than the control group (1.344 0.09222 vs. 3.224 0.4498 mg/ml; p 0.001), and sporadic miscarriage was 2.05 0.28 -fold lower than the control group (1.569 0.1415 vs. 3.224 0.4498 mg/ml; p 0.001, figure). Although a consistent trend could be observed regarding circulating AAT anti-proteolytic activity between the groups, statistical significance was not attained. CONCLUSION: Alpha-1 antitrypsin concentrations are significantly lower in patients with sporadic and recurrent miscarriages compared to normal pregnancies. Accordingly, AAT may play an important role in the pathogenesis of spontaneous pregnancy loss.

Augmentation therapy in alpha-1 antitrypsin deficiency: advances and controversies

Alpha-1 antitrypsin (AAT) deficiency is a hereditary condition characterized by low levels of AAT in plasma and hence diffusion into tissues. One of the most relevant characteristics of the disease is the development of panacinar emphysema due to an imbalance between proteases and antiproteases in the presence of environmental triggers. Left untreated, severe obstructive lung disease may develop. Avoidance of environmental triggers such as cigarette smoking constitutes a critical component of AAT deficiency treatment. Intravenous augmentation therapy is the only specific therapy for the condition that has been approved by the US Food and Drug Administration (FDA). While this therapy likely slows the rate of progression of emphysema and may improve survival in selected individuals with severe AAT deficiency, the gold standard for proof of efficacy is lacking. Areas where controversy exists regarding the use of AAT augmentation therapy include: (1) indications for treatment, (2) selection of specific AAT augmentation therapy, (3) appropriate dose and interval of administration, (4) cost effectiveness, (5) frequency and mode of follow up of treated patients, (6) use of augmentation therapy after lung transplantation, (7) use of recombinant AAT supplementation, (8) alternative delivery routes, and (9) genetic therapy. In this review we describe the advances in treatment and try to address some of the current controversies in AAT deficiency management.