alpha 1-Antitrypsin Deficiency

BackgroundAlpha-1 antitrypsin deficiency (AATD) is a rare hereditary condition that leads to decreased circulating alpha-1 antitrypsin (AAT) levels, significantly increasing the risk of serious lung and/or liver disease in children and adults, in which some aspects remain unresolved.MethodsIn this review, we summarise and update current knowledge on alpha-1 antitrypsin deficiency in order to identify and discuss areas of controversy and formulate questions that need further research.Results1) AATD is a highly underdiagnosed condition. Over 120,000 European individuals are estimated to have severe AATD and more than 90% of them are underdiagnosed.Conclusions2) Several clinical and etiological aspects of the disease are yet to be resolved. New strategies for early detection and biomarkers for patient outcome prediction are needed to reduce morbidity and mortality in these patients; 3) Augmentation therapy is the only specific approved therapy that has shown clinical efficacy in delaying the progression of emphysema. Regrettably, some countries reject registration and reimbursement for this treatment because of the lack of larger randomised, placebo-controlled trials. 4) Alternative strategies are currently being investigated, including the use of gene therapy or induced pluripotent stem cells, and non-augmentation strategies to prevent AAT polymerisation inside hepatocytes.

BackgroundThe 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).MethodsLongitudinal clinical and laboratory data were obtained from the Swedish National registers, by cross-linkage between the Swedish national AATD register, the Swedish National Patient Register, the National Cancer Register and the National Causes of Death Register.ResultsA total of 1595 PiZZ individuals were included in the analyses. The mean follow-up time was 12 years (range 0.3-24). The mean number of follow-ups was 5 (range 2-15). Two or more liver function tests (LFTs) were available in 1123 individuals, and 26% of them (n = 290) had repeated elevated LFTs during the follow-up. The prevalence of any liver disease was 10% (n = 155). Liver cirrhosis was found in 7% of the individuals (n = 116) and hepatocellular carcinoma in 2% (n = 29). The mean age at the onset of liver disease was 61 (SD 15) years. In multivariate analyses, the male gender, age over 50 years, repeated elevated LFTs, hepatitis virus infection, and a diagnosis of diabetes were associated with increased risk of developing liver disease in adulthood (p ConclusionThe prevalence of liver disease in adult PiZZ individuals is 10%. Age over 50 years, the male gender, repeated elevated liver enzymes, hepatitis, and the presence of diabetes mellitus are risk factors for developing liver disease.

Airway inflammation plays a central role in bronchiectasis. Protease-antiprotease balance is crucial in bronchiectasis pathophysiology and increased presence of unopposed proteases activity may contribute to bronchiectasis onset and progression. Proteases' over-reactivity and antiprotease deficiency may have a role in increasing inflammation in bronchiectasis airways and may lead to extracellular matrix degradation and tissue damage. Imbalances in serine proteases and matrix-metallo proteinases (MMPs) have been associated to bronchiectasis. Active neutrophil elastase has been associated with disease severity and poor long-term outcomes in this disease. Moreover, high levels of MMPs have been associated with radiological and disease severity. Finally, severe deficiency of α1-antitrypsin (AAT), as PiSZ and PiZZ (proteinase inhibitor SZ and ZZ) phenotype, have been associated with bronchiectasis development. Several treatments are under study to reduce protease activity in lungs. Molecules to inhibit neutrophil elastase activity have been developed in both oral or inhaled form, along with compounds inhibiting dipeptydil-peptidase 1, enzyme responsible for the activation of serine proteases. Finally, supplementation with AAT is in use for patients with severe deficiency. The identification of different targets of therapy within the protease-antiprotease balance contributes to a precision medicine approach in bronchiectasis and eventually interrupts and disrupts the vicious vortex which characterizes the disease.

ObjectivesAlpha-1-antitrypsin deficiency (AATD) is a rare genetic disorder leading to chronic obstructive pulmonary disease (COPD). Emphysema is the major structural damage visible on CT scans. However, there is little knowledge on the association between other structural abnormalities, such as bronchiectasis (BE), airway wall thickening (WT) or mucus plugs (MP), and clinical features.Materials and methodsRetrospective study between 2008 and 2022 at one University Hospital of Bordeaux on all consecutive AATD patients. Bronchial and parenchymal alterations were evaluated with an (artificial intelligence) AI-driven Normalized Volume of Airway Abnormalities (NOVAA-CT) scoring system, including BE, WT, MP and emphysema quantifications. We evaluated correlations between forced expiratory volume in 1-s (FEV1%), dyspnea severity through the mMRC scale and the occurrence of at least one exacerbation in the year following CT scan.ResultsFifty-two AATD patients were included (median FEV1: 47% (40-65)). CT features of BE, WT and MP were present in 100%, 94.2% and 59% of the study population, respectively, with a lower versus upper lung predominance (p ConclusionThis study demonstrates that AI-assisted identification of structural airway abnormalities is frequent in AATD patients and carries distinct clinical significance. Among them, WT was the most robust predictor of exacerbations.Key pointsQuestion Emphysema is the major structural damage in alpha-1-antitrypsin deficiency (AATD). Clinical associations of bronchial abnormalities such as bronchiectasis (BE), mucus plugs (MP) and wall thickness (WT) are lacking. Findings Quantitative CT of BE and WT correlated with PFT (p ≤ 0.05), while MP correlated with dyspnea scale (p = 0.01). The best predictor of exacerbation was WT (OR = 1.12 [1.02-1.24]). Clinical relevance AI-assisted identification of bronchial abnormalities is frequent in AATD patients in addition to emphysema alone and carries distinct clinical significance. These findings highlight the importance of comprehensive CT-based evaluations to better characterize disease phenotype and guide clinical management in AATD.