PiZZ Genotype Research Articles

Association of circulating Z-polymer with adverse clinical outcomes and liver fibrosis in adults with alpha-1 antitrypsin deficiency.

Circulating polymerized mutant Z-alpha-1 antitrypsin (Z-polymer) constitutes a characteristic feature in alpha-1 antitrypsin deficiency (AATD), but there is limited knowledge about its association with adverse clinical outcomes and liver fibrosis. We explored this association using data from a large cohort of adults with AATD. A total of 836 (431 PiZZ, 405 PiMZ) adults with AATD and 312 controls (PiMM) from the European Alpha-1 Liver Cohort (2015-2020) were included. Time-to-event analyses were conducted for adults with the PiZZ genotype followed for adverse clinical outcomes (earliest occurrence of liver-related hospitalization, liver transplant or all-cause mortality). Cox proportional hazard models were used to describe the association between binary circulating Z-polymer levels and adverse clinical outcomes. Correlations between baseline circulating Z-polymer levels and baseline liver fibrosis (liver stiffness measurement [LSM] determined by transient elastography [FibroScan®]) were evaluated. The analyses were stratified by augmentation therapy status. Of 324 adults with the PiZZ genotype and longitudinal follow-up data, 28 reported adverse clinical outcomes. Higher baseline circulating Z-polymer levels were associated with an increased risk of adverse clinical outcomes in both crude (hazard ratio [95% confidence interval, CI], 2.88 [1.21, 6.87]) and age-adjusted (1.96 [0.78, 4.94]) analyses. In adults with the PiZZ genotype, circulating Z-polymer levels were weakly positively correlated with baseline LSM (Spearman's rho [95% CI]: 0.21 [0.11, 0.31]). Similar results were observed after stratification by augmentation therapy status. In adults with the PiZZ genotype, higher circulating Z-polymer levels were associated with a shorter time to adverse clinical outcome, and positively correlated with baseline LSM. Circulating Z-polymer levels may be a prognostic biomarker of clinically relevant disease in AATD.

The prevalence of bronchiectasis in patients with alpha-1 antitrypsin deficiency: initial report of EARCO

BackgroundAlthough bronchiectasis has been recognised as a feature of some patients with Alpha1-Antitrypsin deficiency the prevalence and characteristics are not widely known. We wished to determine the prevalence of bronchiectasis and patient characteristics. The first cohort of patients recruited to the EARCO (European Alpha1 Research Collaboration) International Registry data base by the end of 2021 was analysed for radiological evidence of both emphysema and bronchiectasis as well as baseline demographic features.ResultsOf the first 505 patients with the PiZZ genotype entered into the data base 418 (82.8%) had a reported CT scan. There were 77 (18.4%) with a normal scan and 38 (9.1%) with bronchiectasis alone. These 2 groups were predominantly female never smokers and had lung function in the normal range. The remaining 303 (72.5%) ZZ patients all had emphysema on the scan and 113 (27%) had additional evidence of bronchiectasis.ConclusionsThe data indicates the bronchiectasis alone is a feature of 9.1% of patients with the PiZZ genotype of Alpha1-antitrypsin deficiency but although emphysema is the dominant lung pathology bronchiectasis is also present in 27% of emphysema cases and may require a different treatment strategy.

Generation of two Alpha-I antitrypsin deficiency patient-derived induced pluripotent stem cell lines ISRM-AATD-iPSC-1 (HHUUKDi011-A) and ISRM-AATD-iPSC-2 (HHUUKDi012-A)

SIX2-positive urine derived renal progenitor cells were isolated from a male and female alpha1-antitrypsin deficiency (AATD) patients both harboring the homozygous PiZZ genotype. The cells were reprogrammed to generate two integration-free induced pluripotent stem cell (iPSC) lines by transfecting episomal-based plasmids expressing OCT4, SOX2, NANOG, c-MYC, KLF4 and LIN28. Pluripotency was confirmed by immunocytochemistry for associated markers and embryoid body-based differentiation into the three germ layers. The iPSC lines carried the parental PiZZ genotype. Comparative transcriptome analyses with human embryonic stem cell line H9 revealed a Pearson correlation of 0.945 for ISRM-AATD-iPSC-1 and 0.939 for ISRM-AATD-iPSC-2 respectively.

Impact of Bronchiectasis on COPD Severity and Alpha-1 Antitrypsin Deficiency as a Risk Factor in Individuals with a Heavy Smoking History.

Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including α1-antitrypsin deficiency and its implications for COPD severity are uncharacterized in such individuals. To characterize the impact of bronchiectasis on COPD and explore α1-antitrypsin as a risk factor for bronchiectasis. SPIROMICS participants (N=914; ages 40-80 years; ≥20 pack-years smoking) had HRCT scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding α1-antritrypsin, SERPINA1, in 835 participants to test for rare variants, focusing on PiZ (Glu366Lys, rs28929474). We identified bronchiectasis in 365 (40%), more frequently in women (45% versus 36%, p=0.0045), older participants (mean age=66[SD=8.3] versus 64[SD=9.1] years, p=0.0083), and those with lower lung function (FEV1%predicted=66%[SD=27] versus 77%[SD=25], p<0.0001; FEV1/FVC=0.54[0.17] versus 0.63[SD=0.16], p<0.0001]. Participants with bronchiectasis had greater emphysema (%voxels ≤-950HFU, 11%[SD=12] versus 6.3%[SD=9], p<0.0001) and PRMfSAD (26[SD=15] versus 19[SD=15], p<0.0001). Bronchiectasis was more frequent in the combined PiZZ and PiMZ genotype groups compared to those without PiZ, PiS, or other rare pathogenic variants (N=21 of 40[52%] versus N=283 of 707[40%], OR=1.97; 95%CI=1.002, 3.90, p=0.049), an association attributed to whites (OR=1.98; 95%CI = 0.9956, 3.9; p=0.051). Bronchiectasis was common in those with heavy smoking histories and was associated with detrimental clinical and radiographic outcomes. Our findings support α1-antitrypsin guideline recommendations to screen for α1-antitrypsin deficiency in an appropriate bronchiectasis subgroup with a significant smoking history.

Impact of Bronchiectasis on COPD Severity and Alpha-1 Antitrypsin Deficiency as a Risk Factor in Individuals with a Heavy Smoking History.

Bronchiectasis is common among those with heavy smoking histories, but risk factors for bronchiectasis, including alpha-1 antitrypsin deficiency, and its implications for COPD severity are uncharacterized in such individuals. To characterize the impact of bronchiectasis on COPD and explore alpha-1antitrypsin as a risk factor for bronchiectasis. SubPopulations and InteRmediate Outcome Measures In COPD Study (SPIROMICS) participants (N=914; ages 40-80 years; ≥20-pack-year smoking) had high-resolution computed tomography (CT) scans interpreted visually for bronchiectasis, based on airway dilation without fibrosis or cicatrization. We performed regression-based models of bronchiectasis with clinical outcomes and quantitative CT measures. We deeply sequenced the gene encoding -alpha-1 antitrypsin, SERPINA1, in 835 participants to test for rare variants, focusing on the PiZ genotype (Glu366Lys, rs28929474). We identified bronchiectasis in 365 (40%) participants, more frequently in women (45% versus 36%, p=0.0045), older participants (mean age=66[standard deviation (SD)=8.3] versus 64[SD=9.1] years, p=0.0083), and those with lower lung function (forced expiratory volume in 1 second [FEV1 ] percentage predicted=66%[SD=27] versus 77%[SD=25], p<0.0001; FEV1 to forced vital capacity [FVC] ratio=0.54[0.17] versus 0.63[SD=0.16], p<0.0001). Participants with bronchiectasis had greater emphysema (%voxels ≤-950 Hounsfield units, 11%[SD=12] versus 6.3%[SD=9], p<0.0001) and parametric response mapping functional small airways disease (26[SD=15] versus 19[SD=15], p<0.0001). Bronchiectasis was more frequent in the combined PiZZ and PiMZ genotype groups compared to those without PiZ, PiS, or other rare pathogenic variants (N=21 of 40 [52%] versus N=283 of 707[40%], odds ratio [OR]=1.97; 95% confidence interval [CI]=1.002, 3.90, p=0.049), an association attributed to White individuals (OR=1.98; 95%CI = 0.9956, 3.9; p=0.051). Bronchiectasis was common in those with heavy smoking histories and was associated with detrimental clinical and radiographic outcomes. Our findings support alpha-1antitrypsin guideline recommendations to screen for alpha-1 antitrypsin deficiency in an appropriate bronchiectasis subgroup with a significant smoking history.

Fazirsiran for Liver Disease Associated with Alpha1-Antitrypsin Deficiency

BackgroundAlpha1-antitrypsin (AAT) deficiency results from carriage of a homozygous SERPINA1 “Z” mutation (proteinase inhibitor [PI] ZZ). The Z allele produces a mutant AAT protein called Z-AAT, which accumulates in hepatocytes and can lead to progressive liver disease and fibrosis. This open-label, phase 2 trial investigated the safety and efficacy of fazirsiran, an RNA interference therapeutic, in patients with liver disease associated with AAT deficiency.MethodsWe assigned adults with the PI ZZ genotype and liver fibrosis to receive fazirsiran at a dose of 200 mg (cohorts 1 [4 patients] and 2 [8 patients]) or 100 mg (cohort 1b [4 patients]) subcutaneously on day 1 and week 4 and then every 12 weeks. The primary end point was the change from baseline to week 24 (cohorts 1 and 1b) or week 48 (cohort 2) in liver Z-AAT concentrations, which were measured by means of liquid chromatography–mass spectrometry.ResultsAll the patients had reduced accumulation of Z-AAT in the liver (median reduction, 83% at week 24 or 48). The nadir in serum was a reduction of approximately 90%, and treatment was also associated with a reduction in histologic globule burden (from a mean score of 7.4 [scores range from 0 to 9, with higher scores indicating a greater globule burden] at baseline to 2.3 at week 24 or 48). All cohorts had reductions in liver enzyme concentrations. Fibrosis regression was observed in 7 of 15 patients and fibrosis progression in 2 of 15 patients after 24 or 48 weeks. There were no adverse events leading to trial or drug discontinuation. Four serious adverse events (viral myocarditis, diverticulitis, dyspnea, and vestibular neuronitis) resolved.ConclusionsIn this small trial, fazirsiran was associated with a strong reduction of Z-AAT concentrations in the serum and liver and concurrent improvements in liver enzyme concentrations. (Funded by Arrowhead Pharmaceuticals; AROAAT-2002 ClinicalTrials.gov number, NCT03946449.)

Shear Wave Elastography and Shear Wave Dispersion Imaging in the Assessment of Liver Disease in Alpha1-Antitrypsin Deficiency.

Liver affection of Alpha1-antitrypsin deficiency (AATD) can lead to cirrhosis and hepatocellular carcinoma (HCC). A noninvasive severity assessment of liver disease in AATD is urgently needed since laboratory parameters may not accurately reflect the extent of liver involvement. Preliminary data exist on two-dimensional shear wave elastography (2D-SWE) being a suitable method for liver fibrosis measurement in AATD. AATD patients without HCC were examined using 2D-SWE, shear wave dispersion imaging (SWD) and transient elastography (TE). Furthermore, liver steatosis was assessed using the controlled attenuation parameter (CAP) and compared to the new method of attenuation imaging (ATI). 29 AATD patients were enrolled, of which 18 had the PiZZ genotype, eight had PiMZ, two had PiSZ and one had a PiZP-Lowell genotype. 2D-SWE (median 1.42 m/S, range 1.14–1.83 m/S) and TE (median 4.8 kPa, range 2.8–24.6 kPa) values displayed a significant correlation (R = 0.475, p < 0.05). 2D-SWE, ATI (median 0.56 dB/cm/MHz, range 0.43–0.96 dB/cm/MHz) and CAP (median 249.5 dB/m, range 156–347 dB/m) values were higher in PiZZ when compared to other AATD genotypes. This study provides evidence that 2D-SWE is a suitable method for the assessment of liver disease in AATD. The newer methods of SWD and ATI require further evaluation in the context of AATD.

Недостаточность альфа-1-антитрипсина: диагностика и лечение (обзор литературы)

Недостаточность альфа-1-антитрипсина - наследственное заболевание, характеризующееся низким уровнем белка альфа-1-антитрипсина (A1AT) в крови. В основном дефицит A1AT проявляется в виде хронической обструктивной болезни легких (ХОБЛ), эмфиземы, а также поражения печени и сосудов. А1АТ является главным ингибитором сериновых протеаз в крови человека. Недостаточность А1АТ обусловлена мутациями в гене SERPINA1. Наиболее распространенными аллельными вариантами в гене SERPINA1 являются S (p.Glu288Val) и Z (р.Glu366Lys), однако в клинической практике большинство случаев тяжелого дефицита А1АТ связаны с генотипом PIZZ. У пациентов с PIZZ патология легких представляет собой фенотип «потери функции», так как дефицит A1AT приводит к ускоренному разрушению паренхимы легких, приводящему к эмфиземе. При Z-мутации 85% синтезированного белка блокируется в гепатоцитах из-за неправильного сворачивания и полимеризации. Накопление полимеризованного белка в эндоплазматической сети гепатоцитов в свою очередь приводит к хроническим заболеваниям печени у некоторых пациентов: циррозу и злокачественным новообразованиям печени. Дефицит А1АТ является довольно распространенным заболеванием, но выявляется лишь незначительная часть лиц с данной патологией. Недостаточность А1АТ зачастую ошибочно диагностируется как ХОБЛ, бронхиальная астма или криптогенное заболевание печени. Задержка в установлении диагноза составляет обычно более 5 лет (в среднем около 8 лет) что, как правило, связано с плохой осведомленностью врачей, недооценкой его распространенности и вариабельностью клинических проявлений. В настоящее время для лечения дефицита А1АТ с легочными проявлениями возможно применение аугментационной терапии, основанной на внутривенном введении очищенного человеческого А1АТ. Также активно ведется поиск новых препаратов, способных улучшить прогноз у пациентов с патологией печени. Современные подходы в лечении дефицита А1АТ, сосредоточенные на генной терапии, становятся перспективным направлением в лечении как легочной, так и печеночной патологии при дефиците А1АТ. Alpha-1 antitrypsin deficiency is a genetic disorder characterized by low level of alfa-1-antitripsin protein (A1AT) in the blood. Usually, A1AT deficiency results in chronic obstructive pulmonary disease (COPD), emphysemas, liver disease and vessels damaging. A1AT is the main inhibitor of serine proteases in human blood. A1AT deficiency is caused by mutations in the gene SERPINA1. The most common SERPINA1 allelic variants are S (p.Glu288Val) and Z (p.Glu366Lys). However, the most of documented severe cases of A1AD are associated with PIZZ genotype. PIZZ genotype patients have loss-of-function phenotype due to accelerated lung parenchyma destruction resulting in emphysema. Z mutation genotype leads to blocking of 85% synthesized protein in hepatocytes due to wrong folding and polymerization. Accumulation of the bodied protein in hepatocytes endoplasmic reticulum results in chronic liver disease, cirrhosis and other liver pathologies. A1AT deficiency is a common disorder, however, this diagnosis is established in a small part of the patients. A1AT deficiency is often misdiagnosed as COPD, asthma or сryptogenic liver disease. Usually, due to underestimating the prevalence of the disease and its unspecific symptoms, the diagnosis delay is more than 5 years (on average about 8 years). Nowadays it is possible to treat lung form of A1AT deficiency used the augmentation therapy, that bases on intravenous infusions of pure human A1AT. Also, the active development of new drugs to improve the prognosis in the patients with liver pathology is ongoing. Modern approaches of A1AT deficiency treatment, focused on gene therapy, are becoming a promising direction in the managing of both pulmonary and hepatic pathology with A1AT deficiency.

Alpha-1 antitrypsin deficiency: an update on clinical aspects of diagnosis and management.

Clinical heterogeneity has been demonstrated in alpha-1 antitrypsin deficiency (AATD), such that clinical suspicion plays an important role in its diagnosis. The PiZZ genotype is the most common severe deficiency genotype and so tends to result in the worst clinical presentation, hence it has been the major focus of research. However, milder genotypes, especially PiSZ and PiMZ, are also linked to the development of lung and liver disease, mainly when unhealthy behaviors are present, such as smoking and alcohol use. Monitoring and managing AATD patients remains an area of active research. Lung function tests or computed tomography (CT) densitometry may allow physicians to identify progressive disease during follow up of patients, with a view to decision making about AATD-specific therapy, like augmentation therapy, or eventually surgical procedures such as lung volume reduction or transplant. Different types of biological markers have been suggested for disease monitoring and therapy selection, although most need further investigation. Intravenous augmentation therapy reduces the progression of emphysema in PiZZ patients and is available in many European countries, but its effect in milder deficiency is less certain. AATD has also been suggested to represent a risk factor and trigger for pulmonary infections, like those induced by mycobacteria. We summarize the last 5–10 years’ key findings in AATD diagnosis, assessment, and management, with a focus on milder deficiency variants.

Liver Involvement in Children with Alpha-1 Antitrypsin Deficiency: A Multicenter Study.

PurposeAlpha-1 antitrypsin deficiency (A1ATD) in one of the most common genetic causes of liver disease in children. We aimed to analyze the clinical characteristics and outcomes of patients with A1ATD.MethodsThis study included patients with A1ATD from five pediatric hepatology units. Demographics, clinical findings, genetics, and outcome of the patients were recorded (n=25).ResultsEight patients (32.0%) had homozygous PiZZ genotype while 17 (68.0%) had heterozygous genotype. Patients with PiZZ genotype had lower alpha-1 antitrypsin levels than patients with PiMZ genotype (37.6±7.7 mg/dL vs. 66.5±22.7 mg/dL, p=0.0001). Patients with PiZZ genotype were diagnosed earlier than patients with PiMZ genotype, but this was not significant (13±6.8 months vs. 23.7±30.1 months, p=0.192). Follow-up revealed the death of one patient (12.5%) with a homozygous mutation, and revealed that one patient had child A cirrhosis, five patients (62.5%) had chronic hepatitis, and one patient (12.5%) was asymptomatic. Nine of the 17 patients with a heterozygous mutation had chronic hepatitis (52.9%), two (11.7%) had child A cirrhosis, and six (35.2%) were asymptomatic. Overall, 18 (72%) of the 25 children had liver pathology in the long-term.ConclusionAlthough prevalence is rare, patients with liver disorders should be checked for alpha-1 antitrypsin levels. Moreover, long-term follow-up is essential because most patients have a liver pathology.

Evaluation of the Efficacy and Safety of VX-814 in Subjects With the PiZZ Genotype

Evaluation of the Efficacy and Safety of VX-814 in Subjects With the PiZZ Genotype

From the Editor’s desk....: August 2018

Alpha-1 antitrypsin deficiency (AATD) is a common genetic disorder causing chronic liver disease. The PiZ mutation results in misfolded alpha-1 antitrypsin protein (Z-AAT) leading to hepatocyte damage and progressive liver disease. It has been proposed that RNAi-based approaches that silence production of hepatic Z-AAT could be useful in these patients. In this issue, Turner et al. performed two important studies. First, they conducted a double-blind, randomised trial in healthy volunteers receiving escalating doses of the investigational agent ARC-AAT. The second study consisted of a randomised trial in 11 PiZZ genotype AATD patients who received ARC-AAT or placebo. A dose-response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and healthy volunteers at 4 mg/kg. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. The authors conclude that PiZZ and healthy volunteers responded similarly to ARC-AAT with a remarkable knockdown of hepatic AAT production. This promising approach should be tested in future studies that modify the drug vehicle. Corrigendum to “From the Editor’s Desk August 2018” [J Hepatol 69 (2018) 265–268]Journal of HepatologyVol. 69Issue 4PreviewIt has come to our attention that when citing the paper by Ferriero et al. the author’s name was misspelt ‘Ferreiro’ in the text and the figure caption. Please note that the correct name for this author is ‘Ferriero’. In the figure cited for this paper the arrow between Pyruvate and Acetyl-coA should be pointing from Pyruvate to Acetyl-coA, as in the original paper. We apologise for these errors which have now been corrected in the online version of this manuscript. Full-Text PDF

Hepatic-targeted RNA interference provides robust and persistent knockdown of alpha-1 antitrypsin levels in ZZ patients

Alpha-1 antitrypsin deficiency (AATD) is a genetic disorder causing pulmonary and liver disease. The PiZ mutation in AAT (SERPINA1) results in mis-folded AAT protein (Z-AAT) accumulating in hepatocytes, leading to fibrosis and cirrhosis. RNAi-based therapeutics silencing production of hepatic Z-AAT might benefit patients with AATD-associated liver disease. This study evaluated an RNAi therapeutic to silence production of AAT. Part A of this double-blind first-in-human study randomized 54 healthy volunteers (HVs) into single dose cohorts (two placebo: four active), receiving escalating doses of the investigational agent ARC-AAT from 0.38 to 8.0 mg/kg or placebo. Part B randomized 11 patients with PiZZ (homozygous for Z-AAT) genotype AATD, who received up to 4.0 mg/kg of ARC-AAT or placebo. Patients with baseline FibroScan® >11 kPa or forced expiratory volume in one second (FEV1) <60% were excluded. Assessments included safety, pharmacokinetics, and change in serum AAT concentrations. A total of 36 HVs received ARC-AAT and 18 received placebo (part A). Seven PiZZ individuals received ARC-AAT and four received placebo (part B). A dose response in serum AAT reduction was observed at doses ≥4 mg/kg with similar relative reductions in PiZZ patients and HVs at 4 mg/kg and a maximum reduction of 76.1% (HVs) vs. 78.8% (PiZZ) at this dose. The time it took for serum AAT to return to baseline was similar for HV and PiZZ. There were no notable differences between HV and PiZZ safety parameters. The study was terminated early because of toxicity findings related to the delivery vehicle (ARC-EX1) seen in a non-human primate study. PiZZ patients and HVs responded similarly to ARC-AAT. Deep and durable knockdown of hepatic AAT production based on observed reduction in serum AAT concentrations was demonstrated. Accumulation of abnormal proteins in the livers of patients with alpha-1 antitrypsin deficiency may lead to decreased liver function and potentially liver failure. Therapeutics targeting the production of these abnormal proteins may be used to prevent or treat liver disease in patients with alpha-1 antitrypsin deficiency. NCT02363946.

ICS Use May Modify FEV1 Decline in α1-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils

Background: α₁-Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD. Objectives: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV₁ decline in patients with AATD. Methods: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1–18 years). Eosinophilia was defined as a level >0.2 × 10⁹/L, and classified by the frequency of such counts into “always,” “intermittent,” or “never present.” Univariate and multivariate analyses were conducted. Results: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV₁ decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV₁ (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV₁ decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS. Conclusions: Blood eosinophil levels persistently >0.2 × 10⁹/L may be an indication for ICS use in PiZZ AATD in order to reduce FEV₁ decline.

Pathophysiology of Alpha-1 Antitrypsin Deficiency Liver Disease.

Classical alpha-1 antitrypsin (a1AT) deficiency is an autosomal recessive disease associated with an increased risk of liver disease in adults and children, and with lung disease in adults (Teckman and Jain, Curr Gastroenterol Rep 16(1):367, 2014). The vast majority of the liver disease is associated with homozygosity for the Z mutant allele, the so-called PIZZ. These homozygous individuals synthesize large quantities of a1AT mutant Z protein in the liver, but the mutant protein folds improperly during biogenesis and approximately 85% of the molecules are retained within the hepatocytes rather than appropriately secreted. The resulting low, or "deficient," serum level leaves the lungs vulnerable to inflammatory injury from uninhibited neutrophil proteases. Most of the mutant Z protein molecules retained within hepatocytes are directed into intracellular proteolysis pathways, but some molecules remain in the endoplasmic reticulum for long periods of time. Some of these molecules adopt an unusual aggregated or "polymerized" conformation (Duvoix et al., Rev Mal Respir 31(10):992-1002, 2014). It is thought that these intracellular polymers trigger a cascade of intracellular injury which can lead to end-organ liver injury including chronic hepatitis, cirrhosis, and hepatocellular carcinoma (Lindblad et al., Hepatology 46(4):1228-1235, 2007). The hepatocytes with the largest accumulations of mutant Z polymers undergo apoptotic death and possibly other death mechanisms. This intracellular death cascade appears to involve ER stress, mitochondrial depolarization, and caspase cleavage, and is possibly linked to autophagy and redox injury. Cells with lesser burdens of mutant Z protein proliferate to maintain the liver cell mass. This chronic cycle of cell death and regeneration activates hepatic stellate cells and initiates the process of hepatic fibrosis. Cirrhosis and hepatocellular carcinoma then result in some patients. Since not all patients with the same homozygous PIZZ genotype develop end-stage disease, it is hypothesized that there is likely to be a strong influence of genetic and environmental modifiers of the injury cascade and of the fibrotic response.

Lung clearance index for monitoring early lung disease in alpha-1-antitrypsin deficiency

Patients with alpha-1-antitrypsin deficiency (AATD) and a PI-ZZ genotype are at high risk to develop severe emphysema during adulthood. However, little is known about early stages of emphysema and disease manifestation in other PI-types. Spirometry is commonly used for monitoring although early manifestation of emphysema is suspected within the peripheral airways that are not accessible by forced expiratory manoeuvres.We hypothesized that the Lung Clearance Index (LCI) derived from multiple breath nitrogen-washout (N2-washout) is useful to bridge this diagnostic gap. Patients from age 4 years onward and different PI-types performed N2-washout and spirometry. Results were compared to controls.193 patients (4–79 years, 75% PI-ZZ) and 33 controls (8–60 years) were included. Mean (SD) LCI in patients was 9.1 (3.1) and 6.3 (0.6) in controls (p ≤ 0.001). 47% of adult patients with other than PI-ZZ genotypes and 39% of all patients with normal spirometry had abnormal LCIs.The LCI measured by N2-washout discriminates between patients with AATD and controls, reflects AATD related lung disease in all stages and appears to identify early peripheral lung changes in younger age than spirometry.We conclude that a normal spirometry does not exclude presence of AATD related lung disease even in genotypes other than PI-ZZ.

Lung Transplantation in Alpha-1-Antitrypsin Deficiency

Background: Lung transplantation is a therapeutic option for patients with end-stage lung disease and a survival benefit has been described in patients with alpha-1-antitrypsin deficiency (A1ATD). The aims of the current study were to determine the survival and health benefits of lung transplantation in UK patients with A1ATD compared to carefully matched non-transplant patients.Methods: Patients with the PiZZ (alpha-1-antitrypsin deficiency) genotype who had undergone lung transplantation between 1996 and 2011 were identified from the UK A1ATD registry. Lung physiology, health status and survival were compared pre- and post-transplant using carefully matched non-transplant patients.Results: Thirty-two A1ATD patients who had undergone lung transplant were identified. Lung function decline pre-transplant was not different to the closely matched non-transplanted cohort. The transplant group pre-transplant, although matched for FEV1, had lower gas transfer measurements, (mean KCO% predicted 41.0% SE ± 3.86 vs 55.6% SE ± 3.10 p < 0.001) and worse health status (SGRQ mean score 64.2 SE ± 2.5 vs 55.3 SE ± 2.0, p < 0.001). Post-transplant, physiology and health status improved significantly (p < 0.002). However, the post-operative mortality over 5 years was no better than for a second group of non-transplant patients further matched for gas transfer or a third group also matched for SGRQ.Conclusion: Patients who underwent lung transplant had lower gas transfer and quality-of-life pre-transplant compared to non-transplant patients matched for FEV1, age and sex, suggesting that these parameters provide extra information helpful in decision making. Lung transplantation for A1ATD patients significantly improves quality-of-life but not survival.

SERPINA1 PiZ and PiS Heterozygotes and Lung Function Decline in the SAPALDIA Cohort

BackgroundSevere alpha1-antitrypsin (AAT) deficiency is a strong risk factor for COPD. But the impact of gene variants resulting in mild or intermediate AAT deficiency on the longitudinal course of respiratory health remains controversial. There is indication from experimental studies that pro-inflammatory agents like cigarette smoke can interact with these variants and thus increase the risk of adverse respiratory health effects. Therefore, we tested the effect of the presence of a protease inhibitor (Pi) S or Z allele (PiMS and PiMZ) on the change in lung function in different inflammation-exposed subgroups of a large, population-based cohort study.Methodology and Principal FindingsThe SAPALDIA population includes over 4600 subjects from whom SERPINA1 genotypes for S and Z alleles, spirometry and respiratory symptoms at baseline and after 11 years follow-up, as well as proxies for inflammatory conditions, such as detailed smoking history, obesity and high sensitivity C-reactive protein (hs-CRP), were available. All analyses were performed by applying multivariate regression models. There was no overall unfavourable effect of PiMS or PiMZ genotype on lung function change. We found indication that PiZ heterozygosity interacted with inflammatory stimuli leading to an accelerated decline in measures in use as indices for assessing mild airway obstruction. Obese individuals with genotype PiMM had an average annual decline in the forced mid expiratory flow (ΔFEF25-75%) of 58.4 ml whereas in obese individuals with PiMZ it amounted to 92.2 ml (p = 0.03). Corresponding numbers for persistent smokers differed even more strongly (66.8 ml (PiMM) vs. 108.2 ml (PiMZ), p = 0.005). Equivalent, but less strong associations were observed for the change in the FEV1/FVC ratio.ConclusionsWe suggest that, in addition to the well established impact of the rare PiZZ genotype, one Z allele may be sufficient to accelerate lung function decline in population subgroups characterized by elevated levels of low grade inflammation.

Outdoor air pollution is associated with rapid decline of lung function in α-1-antitrypsin deficiency

IntroductionOutdoor air pollutants are associated with respiratory morbidity and mortality, but little longitudinal work has been undertaken in this area in chronic obstructive pulmonary disease (COPD). Patients with α-1-antitrypsin deficiency...

Alpha-1-Antitrypsin-Mangel: Update

The time delay between the start of respiratory symptoms and the correct diagnosis of alpha-1-antitrypsin (AAT) deficiency is often 6 to 8 years. Most patients are misdiagnosed as having COPD or asthma. Recent estimates suggest that only 15 % of patients have already been identified. The PiZZ genotype leads to severely decreased AAT serum concentrations, and is associated with a high risk of pulmonary emphysema. Disease manifestation is earlier in smokers than in non-smokers. Since cigarette smoke is able to reduce AAT activity by a factor of 2000, it can accelerate the progression of emphysema. Patients are therefore recommended to stop smoking. The EXACTLE study assessed the development of emphysema by means of CT densitometry in 77 patients with severe AAT deficiency over a period of 2.5 years. CT densitometry was able to detect the progressive loss of lung tissue, and it was found to be more sensitive than pulmonary function or quality of life variables. With weekly intravenous supplementation of alpha-1-antitrypsin, emphysema progressed more slowly compared to placebo (albumin) infusions. In Germany, of about 900 patients are currently receiving supplementation therapy with human AAT. The treatment is well tolerated and well accepted by the patients. Symptomatic treatment consists of long- and short-acting beta-agonists, anticholinergic bronchodilators, and inhaled corticosteroids. Alpha-1 centres provide particular expertise, and it is recommended that every patient should be seen in one of these specialised outpatient clinics.