The spectrum of clinical sequelae associated with alpha-1 antitrypsin deficiency

Abstract

Alpha-1 antitrypsin (AAT) deficiency (AATD) is an autosomal co-dominant condition that predisposes to the development of lung disease, primarily emphysema. Emphysema results from the breakdown of lung matrix elastin by proteases, including neutrophil elastase, a protease normally inhibited by AAT. AATD also predisposes to liver (cirrhosis) and skin (panniculitis) disease, and to vasculitis. The prevalence of AATD is estimated to be approximately 1 in 3,500 individuals in the United States. However, lack of awareness of AATD among some physicians, misperceptions regarding the absence of effective therapy, and the close overlap in symptoms with asthma and non-AATD chronic obstructive pulmonary disease are thought to contribute to under-recognition of the disease. In patients with AATD, treatment with intravenous AAT augmentation therapy is the only currently available treatment known to slow the progression of emphysema. Moreover, smoking cessation and other lifestyle interventions also help improve outcomes. Early diagnosis and intervention are of key importance due to the irreversible nature of the resultant emphysema. Liver disease is the second leading cause of death among patients with AATD and a minority of patients present with panniculitis or antineutrophil cytoplasmic antibody-associated vasculitis, thought to be directly related to AATD. Though no randomized trial has assessed the effectiveness of augmentation therapy for AATD-associated panniculitis, clinical experience and case series suggest there is a benefit. Other diseases putatively linked to AATD include aneurysmal disease and multiple neurological conditions, although these associations remain speculative in nature.

Structural characterization and conformational dynamics of alpha-1 antitrypsin pathogenic variants causing alpha-1-antitrypsin deficiency

“…The SERPINA1 gene is located on chromosome 14q32.1 and has three untranslated exons (IA, IB and IC) and four coding exons (II–V). The first three exons regulate gene expression through three alternative transcription initiation sites: exons IA or IB in macrophages, exon IC in hepatocytes ( Duvoix et al, 2014 ; Greulich et al, 2017 ; Tejwani and Stoller, 2021 ). Pathogenic variants in the SERPINA1 gene underlie alpha-1-antitrypsin deficiency (A1ATD), which causes reduced protein levels.…”

“…A proportion of A1ATD patients develop liver cirrhosis, which may be caused by aggregates of alpha-1-antitrypsin proteins ( Köhnlein and Welte, 2008 ). While it is often undiagnosed ( Quinn et al, 2020 ), it causes emphysema, which can be exacerbated by tobacco smoke ( Tejwani and Stoller, 2021 ). It affects 1 in 2,500 people of European ancestry ( Greulich et al, 2017 ).…”

Molecular Level Atomistic and Structural Insights on Biological Macromolecules, Inhibition, and Dynamics Studies

“…The SERPINA1 gene is located on chromosome 14q32.1 and has three untranslated exons (IA, IB and IC) and four coding exons (II-V). The first three exons regulate gene expression through three alternative transcription initiation sites: exons IA or IB in macrophages, exon IC in hepatocytes (Duvoix et al, 2014;Greulich et al, 2017;Tejwani and Stoller, 2021). Pathogenic variants in the SERPINA1 gene underlie alpha-1antitrypsin deficiency (A1ATD), which causes reduced protein levels.…”

Promising Neutrophil-Associated Biomarkers in Lung Diseases of Patients with Antisynthetase Syndrome and Dermatomyositis

“…AAT is an important inhibitor of the protease, neutrophil elastase, which results in the breakdown of lung matrix elastin. And AAT deficiency (AATD) is a common reason for emphysema and thought to be an important factor in maintaining structural stability of the lung [ 40 ]. Our results found no clear implication of AAT for either RP-ILD or respiratory infections, while AAT showed a negative correlation with FVC in the study of lung function.…”