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Alpha-1-Antitrypsin Deficiency

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1. Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. (PubMed)

Intravenous alpha-1 antitrypsin augmentation therapy for treating patients with alpha-1 antitrypsin deficiency and lung disease. Alpha-1 antitrypsin deficiency is an inherited disorder that can cause chronic obstructive pulmonary disease (COPD). People who smoke are more seriously affected and have a greater risk of dying from the disease. Therefore, the primary treatment is to help people give up smoking. There are now also preparations available that contain alpha-1 antitrypsin (...) , but it is uncertain what their clinical effect is.To review the benefits and harms of augmentation therapy with intravenous alpha-1 antitrypsin in patients with alpha-1 antitrypsin deficiency and lung disease.We searched the Cochrane Central Register of Controlled Trials (CENTRAL), PubMed and ClinicalTrials.gov to 25 March 2016.We included randomised trials of augmentation therapy with alpha-1 antitrypsin compared with placebo or no treatment.The two review authors independently selected trials, extracted outcome

2016 Cochrane

3. Alpha-1 antitrypsin deficiency

Alpha-1 antitrypsin deficiency Alpha-1 antitrypsin deficiency - Symptoms, diagnosis and treatment | BMJ Best Practice You'll need a subscription to access all of BMJ Best Practice Search  Alpha-1 antitrypsin deficiency Last reviewed: February 2019 Last updated: March 2018 Summary Genetic disorder with an autosomal inheritance pattern and codominant expression of alleles. Pulmonary and hepatic manifestations include emphysema, COPD, and cirrhosis. Granulomatosis with polyangiitis (formerly (...) known as Wegener's granulomatosis) and necrotising panniculitis are infrequent complications but can prompt diagnosis. Plasma AAT levels, protein phenotyping (called Pi-typing), and protein genotyping may be necessary for diagnosis. Rare alleles may require gene sequencing. Intravenous AAT augmentation therapy benefits some patients. Definition Alpha-1 antitrypsin (AAT) deficiency is an autosomal codominant genetic disorder (i.e., 1 allele is inherited from each parent and each allele is expressed

2018 BMJ Best Practice

4. Efficacy and safety of inhaled alpha-1-antitrypsin in patients with severe alpha-1-antitrypsin deficiency and frequent exacerbations of Chronic Obstructive Pulmonary Disease. (PubMed)

Efficacy and safety of inhaled alpha-1-antitrypsin in patients with severe alpha-1-antitrypsin deficiency and frequent exacerbations of Chronic Obstructive Pulmonary Disease. Patients with inherited alpha-1-antitrypsin (AAT) deficiency (ZZ-AATD) and severe chronic obstructive pulmonary disease (COPD) frequently suffer from exacerbations. We postulated that inhalation of nebulised AAT would be an effective treatment.We randomly assigned 168 patients to receive twice daily inhalations of 80 mg

2019 European Respiratory Journal

5. Alpha-1 antitrypsin (Respreeza) for emphysema associated with alpha-1 antitrypsin deficiency ? maintenance therapy

Alpha-1 antitrypsin (Respreeza) for emphysema associated with alpha-1 antitrypsin deficiency ? maintenance therapy Alpha-1 antitrypsin (Respreeza) for emphysema associated with alpha-1 antitrypsin deficiency – maintenance therapy Alpha-1 antitrypsin (Respreeza) for emphysema associated with alpha-1 antitrypsin deficiency – maintenance therapy NIHR HSC Record Status This is a bibliographic record of a published health technology assessment from a member of INAHTA. No evaluation of the quality (...) of this assessment has been made for the HTA database. Citation NIHR HSC. Alpha-1 antitrypsin (Respreeza) for emphysema associated with alpha-1 antitrypsin deficiency – maintenance therapy. Birmingham: NIHR Horizon Scanning Centre (NIHR HSC). Horizon Scanning Review. 2014 Final publication URL Indexing Status Subject indexing assigned by CRD MeSH Emphysema; Pulmonary Emphysema; alpha 1-Antitrypsin; alpha 1-Antitrypsin Deficiencys Language Published English Country of organisation England English summary

2014 Health Technology Assessment (HTA) Database.

6. Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications (PubMed)

Alpha 1 antitrypsin to treat lung disease in alpha 1 antitrypsin deficiency: recent developments and clinical implications Alpha 1 antitrypsin deficiency is a hereditary condition characterized by low alpha 1 proteinase inhibitor (also known as alpha 1 antitrypsin [AAT]) serum levels. Reduced levels of AAT allow abnormal degradation of lung tissue, which may ultimately lead to the development of early-onset emphysema. Intravenous infusion of AAT is the only therapeutic option that can be used (...) the course of disease progression was demonstrated for the first time in the Randomized, Placebo-controlled Trial of Augmentation Therapy in Alpha-1 Proteinase Inhibitor Deficiency (RAPID) trial. Following these results, an expert review forum was held at the European Respiratory Society to discuss the findings of the RAPID trial program and how they may change the landscape of alpha 1 antitrypsin emphysema treatment. This review summarizes the results of the RAPID program and the implications

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2018 International journal of chronic obstructive pulmonary disease

7. Mineralization of alpha-1-antitrypsin inclusion bodies in Mmalton alpha-1-antitrypsin deficiency (PubMed)

Mineralization of alpha-1-antitrypsin inclusion bodies in Mmalton alpha-1-antitrypsin deficiency Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton (...) variant as on IEF profile it resembles the wild M2 subtype.This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations.Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules

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2018 Orphanet journal of rare diseases

8. Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population. (PubMed)

Characterisation of a type II functionally-deficient variant of alpha-1-antitrypsin discovered in the general population. Lung disease in alpha-1-antitrypsin deficiency (AATD) results from dysregulated proteolytic activity, mainly by neutrophil elastase (HNE), in the lung parenchyma. This is the result of a substantial reduction of circulating alpha-1-antitrypsin (AAT) and the presence in the plasma of inactive polymers of AAT. Moreover, some AAT mutants have reduced intrinsic activity toward (...) of the RCL into β-sheet A. Identification of a fully dysfunctional AAT mutant that does not show a secretory defect underlines the importance of accurate genotyping of patients with pulmonary AATD manifestations regardless of the presence of normal levels of AAT in the circulation. This subtype of disease is reminiscent of dysfunctional phenotypes in anti-thrombin and C1-inibitor deficiencies so, accordingly, we classify this variant as the first pure functionally-deficient (type II) AATD mutant.

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2019 PLoS ONE

9. Bioequivalence of a Liquid Formulation of Alpha<sub>1</sub>-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha<sub>1</sub>-PI) in Alpha<sub>1</sub>-Antitrypsin Deficiency. (PubMed)

Bioequivalence of a Liquid Formulation of Alpha1-Proteinase Inhibitor Compared with Prolastin®-C (Lyophilized Alpha1-PI) in Alpha1-Antitrypsin Deficiency. This study evaluated the bioequivalence, safety, and immunogenicity of a new liquid formulation of human plasma-derived alpha1-proteinase inhibitor, Liquid Alpha1-PI, compared with the Lyophilized Alpha1-PI formulation (Prolastin®-C), for augmentation therapy in patients with alpha1-antitrypsin deficiency

2017 COPD

10. Liver disease in adults with severe alpha-1-antitrypsin deficiency. (PubMed)

Liver disease in adults with severe alpha-1-antitrypsin deficiency. The proportion of adults with liver disease due to severe alpha-1-antitrypsin deficiency (AATD), with PiZZ phenotype, is not clear. The markers of the AATD liver disease, how it progresses, and measures for its prevention have not been established. The aim of this study was to analyze the risk of liver disease in individuals with severe AAT deficiency (PiZZ).Longitudinal clinical and laboratory data were obtained from

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2019 Journal of gastroenterology

11. Alpha-1 antitrypsin deficiency liver disease, mutational homogeneity modulated by epigenetic heterogeneity with links to obesity. (PubMed)

Alpha-1 antitrypsin deficiency liver disease, mutational homogeneity modulated by epigenetic heterogeneity with links to obesity. Alpha-1 Antitrypsin Deficiency (AATD) liver disease is characterized by marked heterogeneity in presentation and progression despite a common underlying gene mutation, strongly suggesting the involvement of other genetic and/or epigenetic modifiers. Variation in clinical phenotype has added to the challenge of detection, diagnosis, and testing of new therapies

2019 Hepatology

12. Limited GPA and Alpha-1 Antitrypsin Deficiency in a Pediatric Patient. (PubMed)

Limited GPA and Alpha-1 Antitrypsin Deficiency in a Pediatric Patient. Granulomatosis with polyangiitis (GPA) is a rare systemic vasculitis affecting small to medium-sized blood vessels. The most frequent presenting symptoms are nonspecific constitutional symptoms, followed by pulmonary, renal, and upper respiratory tract symptoms1.

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2019 Journal of Rheumatology

13. Clinical impact of alpha-1-antitrypsin deficiency in ANCA-associated vasculitis: results from a French retrospective monocentric cohort of 142 consecutive patients. (PubMed)

Clinical impact of alpha-1-antitrypsin deficiency in ANCA-associated vasculitis: results from a French retrospective monocentric cohort of 142 consecutive patients. Deficiency in alpha-1-antitrypsin (AAT) is a possible pathogenic cofactor in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). However, the clinical impact of AAT deficiency remains poorly established in this setting. This study aimed to describe the clinical phenotypes and outcomes of AAV according to AAT (...) -polymerogenic M-variant phenotype, 18 (13%) had MZ, 12 (8%) had MS, 2 (1%) had ZZ, 2 (1%) had SZ and 1 (1%) had SS. M, Z and S allele frequencies were 84, 8 and 6%, respectively. No association was observed between AAT deficiency and ANCA subtype or AAV phenotype, except for intra-alveolar haemorrhage, which was more frequent in patients harbouring at least one of the deficient Z or S alleles than in those without any deficient alleles (p<0.01). Global, renal or relapse-free survival rates were similar

2019 Journal of Rheumatology

14. Regional lung densities in alpha-1 antitrypsin deficiency compared to predicted values. (PubMed)

Regional lung densities in alpha-1 antitrypsin deficiency compared to predicted values. We developed a method to calculate a standard score for lung tissue mass derived from CT scan images from a control group without respiratory disease. We applied the method to images from subjects with emphysema associated with alpha-1 antitrypsin deficiency (AATD) and used it to study regional patterns of differential tissue mass.We explored different covariates in 76 controls. Standardization was applied (...) to facilitate comparability between different CT scanners and a standard Z-score (Standard Mass Score, SMS) was developed, representing lung tissue loss compared to normal lung mass. This normative data was defined for the entire lungs and for delineated apical, central and basal regions. The agreement with DLCO%pred was explored in a data set of 180 patients with emphysema who participated in a trial of alpha-1-antitrypsin augmentation treatment (RAPID).Large differences between emphysematous and normal

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2019 Respiratory research

15. Liver Disease due to Alpha-1 Antitrypsin Deficiency: Are we surprised that it is more complex than we thought? (PubMed)

Liver Disease due to Alpha-1 Antitrypsin Deficiency: Are we surprised that it is more complex than we thought? Alpha-1 antitrypsin deficiency (AATD) resulting from mutations in the SERPINA1 gene is associated with decreased circulating level of alpha-1 antitrypsin, and homozygosity for the Z allele is well-known to result in both lung disease (in the form of emphysema) and liver disease (1). Historically, the liver disease has been described as being different at different times in life. Thus

2019 Hepatology

16. Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease? (PubMed)

Alpha-1 Antitrypsin Deficiency and Accelerated Aging: A New Model for an Old Disease? Alpha-1 antitrypsin (AAT) protects the lung by inhibiting neutrophil proteinases, but AAT has many other non-proteolytic functions that are anti-inflammatory, antiviral and homeostatic. Approximately 1 in 1600 to 1 in 5000 people have the homozygous Z mutation, which causes AAT misfolding, accumulation in (predominantly) liver cells and low circulating levels of AAT, leading to AAT deficiency (AATD). AATD (...) is classically a disease of neutrophilic inflammation, with an aggressive and damaging innate immune response contributing to emphysema and other pathologies. AATD is one of the most common genetic disorders but considerably under-recognised. Most patients are diagnosed later in life, by which time they may have accumulated significant lung, liver and multisystem damage. Disease presentation is heterogeneous and not fully explained by deficiency levels alone or exposure to cigarette smoking. This suggests

2019 Drugs & Aging

17. Increased Frequency of Heterozygous Alpha-1 Antitrypsin Deficiency in Liver Explants from Non-Alcoholic Steatohepatitis Patients. (PubMed)

Increased Frequency of Heterozygous Alpha-1 Antitrypsin Deficiency in Liver Explants from Non-Alcoholic Steatohepatitis Patients. Cirrhotic explanted livers occasionally have unexpected PASD (periodic acid-Schiff-diastase) positive globules within the hepatocyte cytoplasm. It is often unclear whether this finding is a non-specific consequence of cirrhosis or indicative of underlying A1ATD (alpha-1 antitrypsin deficiency) contributing to the cirrhosis. In this study, explanted livers were (...) steatohepatitis, 47%) compared to other causes such as chronic ethanol use (16%) and chronic hepatitis C virus infection (6.7%) (P 0.001). Immunohistochemistry confirmed all PASD+ globules were A1AT positive, with 20 of 21 cases demonstrating diffuse A1AT staining. In an expanded NASH cohort, 42% (14/33) of explants had PASD+ globules, and 92% of these PASD+ cases were homozygous (n=1) or heterozygous (n=11) for the SERPINA1 Z allele, corresponding to nearly 40% of all NASH patients. Overall, the Z allele

2019 Liver Transplantation

18. Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency. (PubMed)

Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency. Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the 'Z' and 'S' variants - single-nucleotide variations (SNVs) that result in amino acid substitutions (...) the potential pathogenicity of these variants; methods included a support vector machine (SVM) program, PolyPhen-2 (Harvard University, Cambridge, MA), and FoldX (Centre for Genomic Regulation, Barcelona, Spain).Samples from 23 patients were analyzed; 21 rare/novel sequence variants were identified by NGS, including splice variants (n = 2), base pair deletions (n = 1), stop codon insertions (n = 2), and SNVs (n = 16). Computational modeling of protein structures caused by the novel SNVs showed that 8 were

2019 BMC Medical Genetics

19. Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence. (PubMed)

Long-term clinical outcomes following treatment with alpha 1-proteinase inhibitor for COPD associated with alpha-1 antitrypsin deficiency: a look at the evidence. Alpha-1 antitrypsin deficiency (AATD) is a common hereditary disorder caused by mutations in the SERPINA1 gene, which encodes alpha-1 antitrypsin (AAT; also known as alpha 1-proteinase inhibitor, A1-PI). An important function of A1-PI in the lung is to inhibit neutrophil elastase, one of various proteolytic enzymes released (...) into prolonged placebo-controlled trials remains a significant obstacle. Despite this, the Randomized, placebo-controlled trial of augmentation therapy in Alpha 1-Proteinase Inhibitor Deficiency (RAPID) and RAPID Extension trial, the largest clinical program completed to date, utilized quantitative chest computed tomography as a sensitive and specific measure of the extent of emphysema. Findings from the RAPID/RAPID Extension program definitively confirmed the benefits of A1-PI therapy in slowing disease

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2017 Respiratory research

20. Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature (PubMed)

Clinical utility of alpha-1 proteinase inhibitor in the management of adult patients with severe alpha-1 antitrypsin deficiency: a review of the current literature Alpha-1 antitrypsin (AAT) functions primarily to inhibit neutrophil elastase, and its deficiency predisposes individuals to the development of chronic obstructive pulmonary disease (COPD). The putative protective serum concentration is generally considered to be above a threshold of 11 μM/L, and therapeutic augmentation of AAT above (...) with a relatively long natural history. Computed tomography has been applied to measure lung density as a more specific and sensitive surrogate outcome measure of emphysema than physiologic indices, such as forced expiratory volume in 1 second, and studies consistently show a therapeutic reduction in the rate of lung density decline. However, convincing evidence of benefit using traditional clinical measures remains elusive. Intravenous administration of AAT at a dose of 60 mg/kg/week is the commonest regime

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2017 Drug design, development and therapy

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