Summary Background Alpha‐1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD. Aims To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review. Methods A comprehensive search was conducted across multiple databases. Two independent authors selected the articles and assessed bias using the Newcastle‐Ottawa Scale. Data were pooled for analysis, where comparable outcomes were reported. Results Thirty‐five studies were identified related to disease progression and 12 for the treatment of AATD. Seven per cent of children were reported to develop liver cirrhosis, with 16.5% of individuals presenting in childhood requiring liver transplantation. Of those surviving to adulthood, 10.5% had liver cirrhosis and 14.7% required transplantation. Liver transplantation was the only effective treatment reported and outcomes compare favourably to other indications, with 5‐year survival reported as over 90% in children and over 80% in adults. Discussion The clinical course of liver disease in individuals with AATD remains poorly understood, but affects about 10% of those with AATD. More research is required to identify those patients at risk of developing liver disease at an early stage, and to provide alternative treatments to liver transplantation.

BackgroundChronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction and accelerated decline of forced expired volume in 1 second (FEV1). Alpha-1-antitrypsin deficiency is a genetic cause of COPD and associated with more rapid decline in lung function, even in some never smokers (NS) but the potential for individualized assessment to reveal differences when compared to group analyses has rarely been considered.MethodsWe analyzed decline in post-bronchodilator FEV1 and gas transfer (% predicted) over at least 3 years (mean= 6.11, 95% CI 5.80–6.41) in our unique data set of 482 patients with alpha-1-antitrypsin deficiency (PiZ) to determine individual rates of decline, implications for prognosis, and potential clinical management.FindingsThere was a marked variation in individual rates of FEV1 decline from levels consistent with normal aging (observed in 23.5% of patients with established COPD, 57.5% of those without) to those of rapidly declining COPD. Gas transfer did not decline in 12.8% of NS and 20.7% of ex-smokers with established COPD (33.3% and 25.0%, respectively, for those without COPD). There was no correlation between decline in gas transfer and FEV1 for those with COPD, although a weak relationship existed for those without (r=0.218; P<0.025).ConclusionThese data confirm differing individual rates of lung function decline in alpha-1-antitrypsin deficiency, indicating the importance of comprehensive physiological assessment and a personalized approach to patient management.

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk.Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV), ratio of FEV/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV were assessed in 196 AATD patients.FEV/FVC, FEV % predicted and lung densitometry related to MMEF % pred (r=0.778, p<0.0001; r=0.787, p<0.0001; r=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV/FVC and MMEF (group 1), normal FEV/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09-39.63) 9.67 (IQR 1.83-22.35); p=0.006) and had a greater subsequent decline in FEV (median change in FEV -1.09% pred per year (IQR -1.91-0.04% pred per year) -0.04% pred per year (IQR -0.67-0.03% pred per year); p=0.007).A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV.

Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).

BackgroundAlpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management.MethodsStandard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology.ResultsIn all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema.ConclusionIntravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.

Rate of change in lung densitometry could predict survival in A1ATD.

AimTo investigate associations between periodontitis and chronic obstructive pulmonary disease (COPD) with and without alpha‐1 antitrypsin deficiency (AATD), including neutrophil functions implicated in tissue damage.MethodsThe presence and severity of periodontitis (using two international criteria) and lung disease were assessed in 156 COPD patients with and without AATD accounting for common confounding factors. Saliva and systemic inflammatory markers were measured by ELISA together with neutrophil migration.ResultsCOPD and AATD patients exhibited higher prevalence of periodontitis (COPD 95%; AATD 88%) than reported in unselected community‐dwelling populations even when risk factors (age, smoking history, socio‐economic status and dental habits) were considered. Periodontitis severity associated with lung disease severity (AATD, periodontitis versus no periodontitis; FEV1 = 56% versus 99% predicted; TLCO = 59% versus 81% predicted, p < .0001 for both). Neutrophil migratory accuracy declined in stage II–IV periodontitis patients with COPD or AATD compared to COPD or AATD with no or stage I periodontitis. Improved dental habits appeared to be associated with a reduction in exacerbation frequency in COPD.ConclusionThe results support shared pathophysiology between periodontitis and COPD, especially when associated with AATD. This may reflect an amplification of neutrophilic inflammation and altered neutrophil functions, already described in periodontitis, COPD and AATD.

BackgroundTrials of disease modifying therapies in Chronic Obstructive Pulmonary Disease (COPD) provide challenges for detecting physiological and patient centred outcomes. The purpose of the current study was to monitor decline in health status in Alpha-1 antitrypsin deficiency (AATD) and determine its’ relationship to conventional physiology.MethodsPatients recruited to the UK-AATD database with a median follow up of 7 years (IQR 5–10) were studied to determine annual change in St George’s Respiratory Questionnaire (SGRQ), FEV1, gas transfer and their feasibility of use in future trials.ResultsAnnual decline in SGRQ had a wide range, was greater for patients with established COPD and correlated with decline in FEV1 (p < 0.0001). Total score decline was greater (p < 0.05) for those with accelerated FEV1 decline (median = 1.07 points/year) compared to those without (median = 0.51). Power calculations indicated effective intervention would not achieve MCID for the SGRQ unless the timeframe was extended for up to 8 years. More than 5000 patients/arm would be required for a statistically significant modest effect over 3 years even in those with rapid FEV1 decline.ConclusionDespite AATD being a rapidly declining form of COPD, deterioration in SGRQ was slow consistent with ageing and the chronic nature of disease progression. Power calculations indicate the numbers needed to detect a difference with disease modifying therapies would be prohibitive especially in this rare cause of COPD. These data have important implications for future study design of disease modifying therapies even in COPD not associated with AATD.Electronic supplementary materialThe online version of this article (10.1186/s12931-018-0844-6) contains supplementary material, which is available to authorized users.