Portuguese consensus document for the management of alpha-1-antitrypsin deficiency

Lopes, António Paulo; Mineiro, Alexandra; Costa, Fátima; Gomes, José Melo; Santos, Carlos Pereira dos; Antunes, C.; Maia, Dionísio; Melo, Ricardo; Canotilho, Maria; Magalhães, Eunice; Vicente, Inês Nunes; Valente, Carla; Gonçalves, Bruno Gil; Condé, B.; Guimarães, C.; Silva, Célia Regina Sousa da; Amado, Joana; Brandão, Maria Esteves; Sucena, Maria; Oliveira, Maria João; Seixas, Susana; Teixeira, Vicente P.C.; Telo, L.

doi:10.1016/j.pulmoe.2018.09.004

Cited by 30 publications

(45 citation statements)

References 154 publications

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“…9,19 The underlying mechanisms of panniculitis and ANCA vasculitis linked to AATD are not yet fully elucidated, but those are probably correlated with both processes of unbalanced proteolysis and polymer accumulation. 1,6 The SERPINA1 Gene and Its Variants AAT is encoded by SERPINA1 (SERPIN family A member 1) gene, which is located at chromosomal region 14q32.13, and spans for about 13.9 kb (GRCh38.p13/hg38 genomic coordinates chr14: 94,376,390,654). SERPINA1 is organized into seven exons of which the first three are untranslated regions (UTR), often labeled as IA, IB and IC, and the remaining four comprise the coding region and the terminal UTR (exons II-V).…”

Section: Seixas and Marques Dovepressmentioning

confidence: 99%

“…Although in most cases these are translated into a functional protein present in the bloodstream at lower concentrations, some mutations can also lead to dysfunctional molecules or null variants. [1][2][3] The major clinical implications of AATD are an increased risk of chronic obstructive pulmonary disease (COPD) and emphysema in adults, and hepatic illness during childhood or later in adult life. Nonetheless, AATD has been associated with disorders affecting not only the respiratory system but also other organs, such as bronchiectasis, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, and panniculitis.…”

Section: Introductionmentioning

confidence: 99%

“…Nonetheless, AATD has been associated with disorders affecting not only the respiratory system but also other organs, such as bronchiectasis, anti-neutrophil cytoplasmic antibody (ANCA) -associated vasculitis, and panniculitis. 1,[4][5][6][7] AATD has been typically correlated with European populations, where its prevalence can reach up to 1:2000 subjects. 8,9 However, this genetic condition can be virtually detected anywhere due to a worldwide dispersal of two more prevalent deficiency alleles, the S and Z alleles, and a large spectrum of rare pathogenic mutations, which are typically more geographically confined.…”

Section: Introductionmentioning

confidence: 99%

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Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Seixas

Marques

2021

TACG

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Alpha-1-Antitrypsin deficiency (AATD), caused by SERPINA1 mutations, is one of the most prevalent Mendelian disorders among individuals of European descend. However, this condition, which is characterized by reduced serum levels of alpha-1-antitrypsin (AAT) and associated with increased risks of pulmonary emphysema and liver disease in both children and adults, remains frequently underdiagnosed. AATD clinical manifestations are often correlated with two pathogenic variants, the Z allele (p. Glu342Lys) and the S allele (p.Glu264Val), which can be combined in severe ZZ or moderate SZ risk genotypes. Yet, screenings of AATD cases and large sequencing efforts carried out in both control and disease populations are disclosing outstanding numbers of rare SERPINA1 variants (>500), including many pathogenic and other likely deleterious mutations. Generally speaking, pathogenic variants can be subdivided into either loss-or gain-of-function according to their pathophysiological effects. In AATD, the loss-of-function is correlated with an uncontrolled activity of elastase by its natural inhibitor, the AAT. This phenomenon can result from the absence of circulating AAT (null alleles), poor AAT secretion from hepatocytes (deficiency alleles) or even from a modified inhibitory activity (dysfunctional alleles). On the other hand, the gain-of-function is connected with the formation of AAT polymers and their switching on of cellular stress and inflammatory responses (deficiency alleles). Less frequently, the gain-of-function is related to a modified protease affinity (dysfunctional alleles). Here, we revisit SERPINA1 mutation spectrum, its origins and population history with a greater emphasis on variants fitting the aforementioned processes of AATD pathogenesis. Those were selected based on their clinical significance and wider geographic distribution. Moreover, we also provide some directions for future studies of AATD clinically heterogeneity and comprehensive diagnosis.

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Section: Seixas and Marques Dovepressmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Seixas

Marques

2021

TACG

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“…The clinical practice guidelines from the Alpha1 Foundation clearly state that intravenous augmentation therapy is recommended for individuals with a predicted FEV1 less than 30%, and, for those with an FEV1 greater than 65%, they recommend discussing with each individual the potential benefits of reducing lung function decline, considering the cost of the therapy and lack of evidence for its benefits [34]. Similarly, the Portuguese guidelines state that augmentation therapy should not be discontinued in case of pulmonary function deterioration, even if it reaches the lowest established limit for its initiation [35].…”

Section: Lung Function Limitsmentioning

confidence: 99%

Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Lόpez-Campos

Hernández

Eraso

2020

JCM

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Ever since the first studies, restoring proteinase imbalance in the lung has traditionally been considered as the main goal of alpha1 antitrypsin (AAT) replacement therapy. This strategy was therefore based on ensuring biochemical efficacy, identifying a protection threshold, and evaluating different dosage regimens. Subsequently, the publication of the results of the main clinical trials showing a decrease in the progression of pulmonary emphysema has led to a debate over a possible change in the main objective of treatment, from biochemical efficacy to clinical efficacy in terms of lung densitometry deterioration prevention. This new paradigm has produced a series controversies and unanswered questions which face clinicians managing AAT deficiency. In this review, the concepts that led to the approval of AAT replacement therapy are reviewed and discussed under a new prism of achieving clinical efficacy, with the reduction of lung deterioration as the main objective. Here, we propose the use of current knowledge and clinical experience to face existing challenges in different clinical scenarios, in order to help clinicians in decision-making, increase interest in the disease, and stimulate research in this field.

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“…The document provided general guidance and extensive recommendations for the diagnosis and management of AATD. 48…”

Section: The Need For Consistent Recommendations (Diagnosis Treatmenmentioning

confidence: 99%

Alpha-1 Antitrypsin Deficiency: Principles of Care

et al. 2020

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Alpha-1 antitrypsin deficiency is an autosomal co-dominant inherited disorder that results in decreased circulating levels of alpha-1 antitrypsin (also known as alpha-1 proteinase inhibitor) and predisposes affected individuals to early onset lung and liver disease. There is currently no cure for alpha-1 antitrypsin deficiency. However, appropriate treatment and a high standard of clinical care can prevent patients from being seriously affected and having to undergo major medical interventions, such as organ transplantation. Beyond managing the symptoms associated with alpha-1 antitrypsin deficiency, alpha-1 proteinase inhibitor therapy is the only treatment for the condition’s underlying cause. Early diagnosis is important to ensure efficient therapeutic strategies and to minimize further deterioration of lung function. alpha-1 antitrypsin deficiency is under diagnosed globally, partly because the disease has no unique presenting symptoms. This document was prepared by a Portuguese multidisciplinary group and it aims to set out comprehensive principles of care for Alpha-1 antitrypsin deficiency. These include the importance of registries, the need for clinical research, the need for consistent recommendations (regarding diagnosis, treatment and monitoring), the role of reference centres, the requirement for sustained access to treatment, diagnostic and support services, and the role of patient organizations.

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Portuguese consensus document for the management of alpha-1-antitrypsin deficiency

Cited by 30 publications

References 154 publications

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Known Mutations at the Cause of Alpha-1 Antitrypsin Deficiency an Updated Overview of SERPINA1 Variation Spectrum

Implications of a Change of Paradigm in Alpha1 Antitrypsin Deficiency Augmentation Therapy: From Biochemical to Clinical Efficacy

Alpha-1 Antitrypsin Deficiency: Principles of Care

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