Search

Abstract Background Alpha1-antitrypsin (AAT) is a serine protease inhibitor that serves as a counterbalance to the activity of elastases, e.g., neutrophil elastase in lung tissue. AAT deficiency (AATD) is a rare disorder usually arising from mutations to the SERPINA1 gene that codes for AAT. The most common AATD alleles are S and Z which produce ~ 40% and ~ 90% reductions in serum AAT, respectively. Rare genetic variants (> 500 identified) can also be associated with mild to severe AATD. Results This report describes a novel mutation of SERPINA1 producing AATD, which we have designated, Q0RİZE. This mutation was identified in a 44-year-old woman admitted with massive hemoptysis and treated with bronchial artery embolization. Computed tomography revealed centriacinar and panacinar emphysema with prominent air entrapment, atelectasis, and localized bronchiectasis. Serum AAT was

Background: Alpha1-antitrypsin (AAT) is a serine protease inhibitor that serves as a counterbalance to the activity of elastases, e.g., neutrophil elastase in lung tissue. AAT deficiency (AATD) is a rare disorder usually arising from mutations to the SERPINA1 gene that codes for AAT. The most common AATD alleles are S and Z which produce ~ 40% and ~ 90% reductions in serum AAT, respectively. Rare genetic variants (> 500 identified) can also be associated with mild to severe AATD. Results: This report describes a novel mutation of SERPINA1 producing AATD, which we have designated, Q0RİZE. This mutation was identified in a 44-year-old woman admitted with massive hemoptysis and treated with bronchial artery embolization. Computed tomography revealed centriacinar and panacinar emphysema with prominent air entrapment, atelectasis, and localized bronchiectasis. Serum AAT was < 0.27 g/L (below detection limit). Genetic analysis showed homozygous deletion of exons I to III. Conclusions: Although many SERPINA1 variants have been identified, variants with large deletions and identified in a homozygous individual, as seen in this case with Q0RIZE, are uncommon. AATD is an underdiagnosed and undertreated disease. Wider screening of COPD patients could result in earlier diagnosis and treatment that could preserve lung function. [ABSTRACT FROM AUTHOR]

Clinical benefit of Alpha1-Proteinase Inhibitor (Human) (A1-PI) products for Alpha1-antitrypsin deficiency (AATD) is uncertain, based on a systematic review of observational studies and randomized controlled trials (RCTs) in AATD of Alpha1-Proteinase Inhibitor (Human) (A1-PI) products. At the recommended dose, A1-PI products raise its serum concentration but do not normalize levels. Observational studies suggest A1-PI might modestly slow progression of airflow limitation in patients with intermediate airflow obstruction, a finding not confirmed by three placebo-controlled RCTs of limited power, which showed non-significant rates of forced expiratory volume in 1 s (FEV1) change favoring placebo. These RCTs found trends favoring A1-PI in loss of high-resolution computerized tomographic (HRCT) lung density. While two meta-analyses of HRCT lung density change in RCTs achieved significance favoring A1-PI arms, clinical benefit remains uncertain. HRCT lung density measurements don't distinguish changes in measured density due to fluid shifts into and out of the lungs and changes in lung inflammation from those due to progressive loss of alveolar mass. A meta-analysis of RCTs found exacerbations significantly increased in A1-PI groups compared to placebo. No RCTs have shown favorable effects of A1-PI on mortality, FEV1, 6-min walking distance, quality of life, change in diffusion capacity of carbon monoxide (DLCO), or exacerbation frequency. A fourth RCT comparing two dose regimens of A1-PI is underway. RCTs have not provided evidence of clinical benefit in terms of how patients feel, function, or survive. Results have implications for the design of future clinical trials of A1-PI and potentially other products targeting AATD-associated emphysema.

Wilson disease and alpha1-antitrypsin deficiency are two rare genetic diseases that may impact predominantly the liver and/or the brain, and the liver and/or the lung, respectively. The early diagnosis of these diseases is important in order to initiate a specific treatment, when available, ideally before irreversible organ damage, but also to initiate family screening. This review focuses on the non-invasive diagnostic tests available for clinicians in both diseases. These tests are crucial at diagnosis to reduce the potential diagnostic delay and assess organ involvement. They also play a pivotal role during follow-up to monitor disease progression and evaluate treatment efficacy of current or emerging therapies. [ABSTRACT FROM AUTHOR]

Abstract Background Spirometry and conventional chest x-ray have limitations in investigating early emphysema, while computed tomography, the reference imaging method in this context, is not part of routine patient care due to its higher radiation dose. In this work, we investigated a novel low-dose imaging modality, dark-field chest x-ray, for the evaluation of emphysema in patients with alpha1-antitrypsin deficiency. Methods By exploiting wave properties of x-rays for contrast formation, dark-field chest x-ray visualises the structural integrity of the alveoli, represented by a high signal over the lungs in the dark-field image. We investigated four patients with alpha1-antitrypsin deficiency with a novel dark-field x-ray prototype and simultaneous conventional chest x-ray. The extent of pulmonary function impairment was assessed by pulmonary function measurement and regional emphysema distribution was compared with CT in one patient. Results We show that dark-field chest x-ray visualises the extent of pulmonary emphysema displaying severity and regional differences. Areas with low dark-field signal correlate with emphysematous changes detected by computed tomography using a threshold of -950 Hounsfield units. The airway parameters obtained by whole-body plethysmography and single breath diffusing capacity of the lungs for carbon monoxide demonstrated typical changes of advanced emphysema. Conclusions Dark-field chest x-ray directly visualised the severity and regional distribution of pulmonary emphysema compared to conventional chest x-ray in patients with alpha1-antitrypsin deficiency. Due to the ultra-low radiation dose in comparison to computed tomography, dark-field chest x-ray could be beneficial for long-term follow-up in these patients.

The clinical characterization of a null variant of SERPINA1 – PiQ0Heidelberg – resulting in alpha1-antitrypsin (AAT) deficiency is described. This rare mutation (c.-5+5 G > A) has been previously identified but not clinically described. The 77 year-old female patient had GOLD-3, Group B COPD, severe destructive panlobular emphysema and newly observed respiratory failure on exertion at the time the genetic analysis was performed. Serum AAT level was 0.1 g/L (reference 0.9–2.0 g/L). Isoelectric focusing showed only the Z-protein indicating that this was a null mutation. The patient has started AAT replacement. Early screening and identification of AAT deficiency would allow for earlier intervention.

Wilson disease and alpha1-antitrypsin deficiency are two rare genetic diseases that may impact predominantly the liver and/or the brain, and the liver and/or the lung, respectively. The early diagnosis of these diseases is important in order to initiate a specific treatment, when available, ideally before irreversible organ damage, but also to initiate family screening. This review focuses on the non-invasive diagnostic tests available for clinicians in both diseases. These tests are crucial at diagnosis to reduce the potential diagnostic delay and assess organ involvement. They also play a pivotal role during follow-up to monitor disease progression and evaluate treatment efficacy of current or emerging therapies.

The existence of alpha-1 antitrypsin variants with apparently unremarkable phenotypes and serum concentrations, contrasting with a clinical picture suggestive of a severe deficiency, led us to investigate whether in these cases there was a reduction or even suppression of the capacity of alpha-1 antitrypsin to inhibit elastase. To this end, in two different laboratories, we adapted and validated a method for measuring the functional activity of alpha-1 antitrypsin, based on spectrophotometric kinetic analysis of the inhibition by serum alpha-1 antitrypsin of the hydrolytic activity of porcine pancreatic elastase on a chromogenic substrate. This method has proved to be robust, reproducible and transferable and made possible to define, on the basis of an analysis of a hospital population, a functionality index with a confidence interval comprised between 0.87 and 1.2, allowing to identify subjects likely to have a functional deficiency of alpha-1 antitrypsin, whether this deficiency being of a genetic origin without any quantitative or phenotypic translation, or whether being acquired under the effect of external agents (cigarette smoke or viruses).

Background: Sex and gender influence many aspects of chronic obstructive pulmonary disease (COPD). Limited data are available on this topic in alpha-1 antitrypsin deficiency (AATD). We therefore aimed to investigate sex issues in the EARCO registry, a prospective, international, observational cohort study., Methods: Baseline data from PiZZ individuals, enrolled in the registry with complete data on sex and smoking history were analysed by group comparisons and binary logistic regression analyses., Results: 1283 patients with AATD, 49.3% women were analysed. Females reported less tobacco consumption (16.8±12.2 vs. 19.6±14.5 PY, p=0.006), occupational exposures towards gases, dusts or asbestos (p<0.005 each) and consumed less alcohol (5.5±7.6 vs. 8.4±10.3u/week, p<0.001). Females reported COPD (41% vs. 57%, p<0.001) and liver disease (11% vs. 20%, p<0.001) less often. However, they had a higher prevalence of bronchiectasis (24% vs. 13%, p<0.001). Despite better lung function (FEV 1 %pred. 73.6±29.9 vs. 62.7±29.5, p<0.001) females reported a similar symptom burden (CAT 13.4±9.5 vs. 12.5±8.9, p=ns) and exacerbation frequency (at least one in the previous year 30% vs. 26%, p=ns) compared to males. In multivariate analyses, female sex was an independent risk factor for exacerbations in the previous year OR 1.6 p=0.001 in addition to smoking history, COPD, asthma and bronchiectasis and was also identified as risk factors for symptom burden (CAT≥10) OR 1.4 p=0.014 besides age, BMI, COPD and smoking history., Conclusion: Men had higher rates of COPD and liver disease, women were more likely to have bronchiectasis. Women's higher symptom burden and exacerbation frequency suggest they may need tailored treatment approaches., (Copyright © 2024 The Author(s). Published by Elsevier España, S.L.U. All rights reserved.)

Clinical benefit of Alpha 1 -Proteinase Inhibitor (Human) (A 1 -PI) products for Alpha 1 -antitrypsin deficiency (AATD) is uncertain, based on a systematic review of observational studies and randomized controlled trials (RCTs) in AATD of Alpha 1 -Proteinase Inhibitor (Human) (A 1 -PI) products. At the recommended dose, A 1 -PI products raise its serum concentration but do not normalize levels. Observational studies suggest A 1 -PI might modestly slow progression of airflow limitation in patients with intermediate airflow obstruction, a finding not confirmed by three placebo-controlled RCTs of limited power, which showed non-significant rates of forced expiratory volume in 1 s (FEV 1 ) change favoring placebo. These RCTs found trends favoring A 1 -PI in loss of high-resolution computerized tomographic (HRCT) lung density. While two meta-analyses of HRCT lung density change in RCTs achieved significance favoring A 1 -PI arms, clinical benefit remains uncertain. HRCT lung density measurements don't distinguish changes in measured density due to fluid shifts into and out of the lungs and changes in lung inflammation from those due to progressive loss of alveolar mass. A meta-analysis of RCTs found exacerbations significantly increased in A 1 -PI groups compared to placebo. No RCTs have shown favorable effects of A 1 -PI on mortality, FEV 1 , 6-min walking distance, quality of life, change in diffusion capacity of carbon monoxide (DL CO) , or exacerbation frequency. A fourth RCT comparing two dose regimens of A 1 -PI is underway. RCTs have not provided evidence of clinical benefit in terms of how patients feel, function, or survive. Results have implications for the design of future clinical trials of A 1 -PI and potentially other products targeting AATD-associated emphysema., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: L. Ross Pierce, M.D. reports financial support was provided by Midnight Sun Technologies, LLC., (© 2024 The Author.)

Chronic lung disease accounts for a significant global burden with respect to death, disability, and health-care costs. Due to the heterogeneous nature and limited treatment options for these diseases, it is imperative that the cellular and molecular mechanisms underlying the disease pathophysiology are further understood. The lung is a complex organ with a diverse cell population, and each cell type will likely have different roles in disease initiation, progression, and resolution. The effectiveness of a given therapeutic agent may depend on the net effect on each of these cell types. Over the past decade, it has been established that endoplasmic reticulum stress and the unfolded protein response are involved in the development of several chronic lung diseases. These conserved cellular pathways are important for maintaining cellular proteostasis, but their aberrant activation can result in pathology. This review discusses the current understanding of endoplasmic reticulum stress and the unfolded protein response at the cellular level in the development and progression of various chronic lung diseases. We highlight the need for increased understanding of the specific cellular contributions of unfolded protein response activation to these pathologies and suggest that the development of cell-specific targeted therapies is likely required to further decrease disease progression and to promote resolution of chronic lung disease. [ABSTRACT FROM AUTHOR]

AATD is a common inherited disorder associated with an increased risk of developing pulmonary emphysema and liver disease. Many people with AATD‐associated pulmonary emphysema remain undiagnosed and therefore without access to care and counselling specific to the disease. AAT augmentation therapy is available and consists of i.v. infusions of exogenous AAT protein harvested from pooled blood products. Its clinical efficacy has been the subject of some debate and the use of AAT augmentation therapy was recently permitted by regulators in Australia and New Zealand, although treatment is not presently subsidized by the government in either country. The purpose of this position statement is to review the evidence for diagnosis and treatment of AATD‐related lung disease with reference to the Australian and New Zealand population. The clinical efficacy and adverse events of AAT augmentation therapy were evaluated by a systematic review, and the GRADE process was employed to move from evidence to recommendation. Other sections address the wide range of issues to be considered in the care of the individual with AATD‐related lung disease: when and how to test for AATD, changing diagnostic techniques, monitoring of progression, disease in heterozygous AATD and pharmacological and non‐pharmacological therapy including surgical options for severe disease. Consideration is also given to broader issues in AATD that respiratory healthcare staff may encounter: genetic counselling, patient support groups, monitoring for liver disease and the need to establish national registries for people with AATD in Australia and New Zealand. [ABSTRACT FROM AUTHOR]

Cristina Esquinas,1,2 Sabina Janciauskiene,3 Ricardo Gonzalo,4 Gemma Mas de Xaxars,4 Beata Olejnicka,5 Irene Belmonte,6 Miriam Barrecheguren,1 Esther Rodriguez,1 Alexa Nuñez,1 Francisco Rodriguez-Frias,6 Marc Miravitlles1 1Pneumology Department, University Hospital Vall d’Hebron, CIBER de Enfermedades Respiratorias (CIBERES), Barcelona, 2Public Health, Mental, Maternal and Child Health Nursing Department, Faculty of Medicine and Health Sciences, University of Barcelona, Barcelona, Spain; 3Department of Respiratory Medicine, Hannover Medical School, BREATH, German Center for Lung Research (DZL), Hannover, Germany; 4Statistics and Bioinformatics Unit (UEB), Vall d’Hebron Research Institute (VHIR), Barcelona, Spain; 5Department of Experimental Medical Science, Lund University, Lund, Sweden; 6Biochemistry Department, University Hospital Vall d’Hebron, Barcelona, Spain Introduction: COPD has complex etiologies involving both genetic and environmental determinants. Among genetic determinants, the most recognized is a severe PiZZ (Glu342Lys) inherited alpha1-antitrypsin deficiency (AATD). Nonetheless, AATD patients present a heterogeneous clinical evolution, which has not been completely explained by sociodemographic or clinical factors. Here we performed the gene expression profiling of blood cells collected from mild and severe COPD patients with PiZZ AATD. Our aim was to identify differences in messenger RNA (mRNA) and microRNA (miRNA) expressions that may be associated with disease severity. Materials and methods: Peripheral blood mononuclear cells from 12 COPD patients with PiZZ AATD (6 with severe disease and 6 with mild disease) were used in this pilot, high-throughput microarray study. We compared the cellular expression levels of RNA and miRNA of the 2 groups, and performed functional and enrichment analyses using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene-ontology (GO) terms. We also integrated the miRNA and the differentially expressed putative target mRNA. For data analyses, we used the R statistical language R Studio (version 3.2.5). Results: The severe and mild COPD–AATD groups were similar in terms of age, gender, exacerbations, comorbidities, and use of augmentation therapy. In severe COPD–AATD patients, we found 205 differentially expressed genes (DEGs) (114 upregulated and 91 downregulated) and 28 miRNA (20 upregulated and 8 downregulated) compared to patients with mild COPD–AATD disease. Of these, hsa-miR-335-5p was downregulated and 12 target genes were involved in cytokine signaling, MAPK/mk2, JNK signaling cascades, and angiogenesis were much more highly expressed in severe compared with mild patients. Conclusions: Despite the small sample size, we identified downregulated miRNA (hsa-miR-335) and the activation of pathways related to inflammation and angiogenesis on comparing patients with severe vs mild COPD–AATD. Nonetheless, our findings warrant further validation in large studies. Keywords: alpha1-antitrypsin deficiency, COPD, gene expression, miRNAs, integrative analysis

Alfonso Carleo,1,2,* Joanna Chorostowska-Wynimko,3,* Thomas Koeck,4 Harald Mischak,4,5 Małgorzata Czajkowska-Malinowska,6 Adriana Rozy,3 Tobias Welte,1,2 Sabina Janciauskiene1,2 1Department of Respiratory Medicine, Hannover Medical School, 2Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), DZL Hannover, Germany; 3Department of Genetics and Clinical Immunology, National Institute of Tuberculosis and Lung Diseases, Warsaw, Poland; 4Mosaiques Diagnostics and Therapeutics AG, Hannover, Germany; 5Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK; 6Department of Lung Diseases and Respiratory Failure, Regional Center of Pulmonology, Bydgoszcz, Poland *These authors contributed equally to this work Abstract: Differentiating between chronic obstructive pulmonary disease (COPD) patients with normal (PiMM) or deficient (PiZZ) genetic variants of alpha-1 antitrypsin (A1AT) is important not only for understanding the pathobiology of disease progression but also for improving personalized therapies. This pilot study aimed to investigate whether urinary peptides reflect the A1AT-related phenotypes of COPD. Urine samples from 19 clinically stable COPD cases (7 PiMM and 12 PiZZ A1AT) were analyzed by capillary electrophoresis coupled to mass spectrometry. We identified 66 peptides (corresponding to 36 unique proteins) that differed between PiZZ and PiMM COPD. Among these, peptides from the collagen family were the most abundant and divergent. A logistic regression model based on COL1A1 or COL5A3 peptides enabled differentiation between PiMM and PiZZ groups, with a sensitivity of 100% and specificity of 85.71% for COL1A1 and a sensitivity of 91.67% and specificity of 85.71% for COL5A3. Furthermore, patients with PiZZ presented low levels of urinary peptides involved in lipoproteins/lipids and retinoic acid metabolism, such as apolipoprotein A-I and C4, retinol-binding protein 4 and prostaglandin-H2 d-isomerase. However, peptides of MDS1 and EVII complex locus, gelsolin and hemoglobin alpha were found in the urine of COPD cases with PiZZ, but not with PiMM. These capillary electrophoresis coupled to mass spectrometry-based results provide the first evidence that urinary peptide content differs between PiMM and PiZZ patients with COPD. Keywords: alpha-1 antitrypsin, alpha-1 antitrypsin deficiency, COPD, urine, peptidomics, capillary electrophoresis coupled to mass spectrometry, phenotypes, peptides, biomarkers, collagen

Tuberculosis (TB) is a major global health problem. Awareness of liver injury due to anti-TB therapy is vital because fulminant hepatic failure is a devastating and often fatal condition without liver transplantation. Here, we report for the first time, two patients of fatal liver injury due to anti-TB drugs in the presence of alpha-1 antitrypsin deficiency. Based on the triad of rapid loss in hepatocyte function, the onset of hepatic encephalopathy, and absence of a prior history of liver disease, the diagnosis of acute liver failure was established. Both patients had low levels of serum alpha-1 antitrypsin, consistent with alpha-1 antitrypsin deficiency. Despite aggressive medical therapy and supportive care, patients developed multi-organ failure and died. It seems measuring the serum levels of alpha 1-antitrypsin before beginning anti-TB therapies is necessary, especially when there is emphysema or bronchiectasis.

Hanan A Tanash,1 Magnus Ekström,2 Philippe Wagner,3 Eeva Piitulainen1 1Department of Respiratory Medicine, Skåne University Hospital, 2Department of Respiratory Medicine, Blekinge Hospital Karlskrona, Lund University, Lund, 3Centre for Clinical Research, Västmanland, Uppsala University, Uppsala, Sweden Background: Severe alpha 1-antitrypsin deficiency (PiZZ) predisposes to morbidity and mortality due to early-onset emphysema and liver disease. The risk of death from other causes, including cardiovascular disease and cancer, has not been well investigated. We aimed to analyze cause-specific mortality in PiZZ individuals compared with the general Swedish population. Methods: Data on 1,561 PiZZ individuals from the Swedish National AAT Deficiency Register, prospectively followed from 1991 to 2014, were analyzed. Causes of death according to the Swedish National Causes of Death Register for the study group were compared with those for the general Swedish population matched for age, sex, and calendar year, with the excess mortality expressed as standardized mortality ratios (SMRs) with 95% confidence intervals (CIs). Results: There were 524 deaths during the follow-up period. PiZZ individuals had excess all-cause mortality compared with the Swedish general population (SMR 3.6, 95% CI 3.3–3.9). SMR for ischemic heart disease (IHD) was 0.5 (95% CI 0.3–0.8) and was similar for never and ever-smokers, and in males and females. SMR for lung cancer was 0.9 (95% CI 0.4–1.7). PiZZ individuals had increased mortality compared with the general population for the following diseases: respiratory disease, SMR 48.4 (95% CI 43.0–54.5); primary liver carcinoma, SMR 90.0 (95% CI 59.3–130.9); complicated colon diverticulitis, SMR 20.8 (95% CI 6.7–48.6); and pulmonary embolism, SMR 6.9 (95% CI 3.3–12.7). Conclusion: PiZZ individuals had a reduced mortality risk of IHD. Mortality due to respiratory, hepatic disease, diverticulitis, and pulmonary embolism was markedly increased compared with the age- and sex-matched Swedish population. Keywords: alpha 1-antitrypsin deficiency, cause-specific mortality, ischemic heart disease, pulmonary embolism, standardized mortality ratio

The aim of the present report is to review the literature addressing the methods developed for the purification of alpha1-antitrypsin (AAT) from the 1950s to the present. AAT is a glycoprotein whose main function is to protect tissues from human neutrophil elastase (HNE) and other proteases released by neutrophils during an inflammatory state. The lack of this inhibitor in human serum is responsible for the onset of alpha1-antitrypsin deficiency (AATD), which is a severe genetic disorder that affects lungs in adults and for which there is currently no cure. Being used, under special circumstances, as a medical treatment of AATD in the so-called “replacement” therapy (consisting in the intravenous infusion of the missing protein), AAT is a molecule with a lot of therapeutic importance. For this reason, interest in AAT purification from human plasma or its production in a recombinant version has grown considerably in recent years. This article retraces all technological advances that allowed the manufacturers to move from a few micrograms of partially purified AAT to several grams of highly purified protein. Moreover, the chronic augmentation and maintenance therapy in individuals with emphysema due to congenital AAT deficiency (current applications in the clinical setting) is also presented.

Cellular homeostasis requires selective autophagic degradation of damaged or defective organelles, including the endoplasmic reticulum (ER). Previous studies have shown that specific ER transmembrane receptors recruit LC3 on autophagic membranes by using LC3-interacting domains. In this study, we showed that the N-degron pathway mediates ubiquitin (Ub)-dependent reticulophagy. During this 2-step process, the ER transmembrane E3 ligase TRIM13 undergoes auto-ubiquitination via lysine 63 (K63) linkage chains and acts as a ligand for the autophagic receptor SQSTM1/p62 (sequestosome 1). In parallel, ER-residing molecular chaperones, such as HSPA5/GRP78/BiP, are relocated to the cytosol and conjugated with the amino acid L-arginine (Arg) at the N-termini by ATE1 (arginyltransferase 1). The resulting N-terminal Arg (Nt-Arg) binds the ZZ domain of SQSTM1, inducing oligomerization of SQSTM1-TRIM13 complexes and facilitating recruitment of LC3 on phagophores to the sites of reticulophagy. We developed small molecule ligands to the SQSTM1 ZZ domain and demonstrate that these chemical mimics of Nt-Arg facilitate reticulophagy and autophagic protein quality control of misfolded aggregates in the ER. [ABSTRACT FROM AUTHOR]

Summary Hepatocytes synthesise the majority of serum proteins. This production occurs in the endoplasmic reticulum (ER) and is adjusted by complex local and systemic regulatory mechanisms. Accordingly, serum levels of hepatocyte-made proteins constitute important biomarkers that reflect both systemic processes and the status of the liver. For example, C-reactive protein is an established marker of inflammatory reaction, whereas transferrin emerges as a liver stress marker and an attractive mortality predictor. The high protein flow through the ER poses a continuous challenge that is handled by a complex proteostatic network consisting of ER folding machinery, ER stress response, ER-associated degradation and autophagy. Various disorders disrupt this delicate balance and result in protein accumulation in the ER. These include chronic hepatitis B infection with overproduction of hepatitis B surface antigen or inherited alpha1-antitrypsin deficiency that give rise to ground glass hepatocytes and alpha1-antitrypsin aggregates, respectively. We review these ER storage disorders and their downstream consequences. The interaction between proteotoxic stress and other ER challenges such as lipotoxicity is also discussed. Collectively, this article aims to sharpen our view of liver hepatocytes as the central hubs of protein metabolism. [ABSTRACT FROM AUTHOR]

CRISPR (clustered regularly interspaced short palindromic repeats) genome editing holds promise in the treatment of genetic diseases that currently lack effective long-term therapies. Patients with alpha-1 antitrypsin (AAT) deficiency develop progressive lung disease due to the loss of AAT's antiprotease function and liver disease due to a toxic gain of function of the common mutant allele. However, it remains unknown whether CRISPR-mediated AAT correction in the liver, where AAT is primarily expressed, can correct either or both defects. Here we show that AAV delivery of CRISPR can effectively correct Z-AAT mutation in the liver of a transgenic mouse model. Specifically, we co-injected two AAVs: one expressing Cas9 and another encoding an AAT guide RNA and homology-directed repair template. In both neonatal and adult mice, this treatment partially restored M-AAT in the serum. Furthermore, deep sequencing confirmed both indel mutations and precise gene correction in the liver, permitting careful analysis of gene editing events in vivo. This study demonstrates a proof of concept for the application of CRISPR-Cas9 technology to correct AAT mutations in vivo and validates continued exploration of this approach for the treatment of patients with AAT deficiency. [ABSTRACT FROM AUTHOR]

Several metabolic monogenic diseases may be cured by liver transplantation alone (LTA) or by combined liver–kidney transplantation (CLKT) when the metabolic disease has caused end-stage renal disease. Liver transplantation may be regarded as a substitute for an injured liver or as supplying a tissue that may replace a mutant protein. Two groups of diseases should be distinguished. In the first group, the kidney tissue may be severely damaged while the liver tissue is almost normal. In this group, renal transplantation is recommended according to the degree of renal damage and liver transplantation is essential as a genetic therapy for correcting the metabolic disorder. In the second group, the liver parenchymal damage is severe. In this group, liver transplantation is essential to avoid liver failure. LTA may also avoid the progression of the renal disease; otherwise a CLKT is needed. In this review, we describe monogenic metabolic diseases involving the kidney that may have beneficial effects from LTA or CLKT. We also highlight the limitations of such procedures and the choice of alternative medical conservative treatments.

Tuberculosis (TB) is a major global health problem. Awareness of liver injury due to anti-TB therapy is vital because fulminant hepatic failure is a devastating and often fatal condition without liver transplantation. Here, we report for the first time, two patients of fatal liver injury due to anti-TB drugs in the presence of alpha-1 antitrypsin deficiency. Based on the triad of rapid loss in hepatocyte function, the onset of hepatic encephalopathy, and absence of a prior history of liver disease, the diagnosis of acute liver failure was established. Both patients had low levels of serum alpha-1 antitrypsin, consistent with alpha-1 antitrypsin deficiency. Despite aggressive medical therapy and supportive care, patients developed multi-organ failure and died. It seems measuring the serum levels of alpha 1-antitrypsin before beginning anti-TB therapies is necessary, especially when there is emphysema or bronchiectasis. [ABSTRACT FROM AUTHOR]

A1AT deficiency- a genetically inherited autosomal codominant disease with more than 120 identified alleles- was first identified by Laurell and Eriksson in 1963. The most common hereditary disorder in adults, A1AT causes an increased risk of developing pulmonary emphysema and liver disease. In A1AT patients, lung disease generally presents at a younger age than “usual” chronic obstructive pulmonary disease (COPD) and it may be misdiagnosed as asthma. Because A1AT deficiency patients can show the same clinical features as non-deficient COPD (including increased evidence of bronchiectasis, frequent exacerbations, impaired health status and a degree of reversibility of airflow obstruction), the World Health Organization recommend to test every patient with a diagnosis of COPD or adult-onset asthma for A1AT deficiency. Despite these recommendations, the epidemiology of A1AT deficiency remains uncertain. Although recently discovered A1AT deficiency has affected human populations since antiquity. By using scientific data and recently studied skeletons and historical cases, we show that it is now possible to reconstruct the natural history of pathological processes, whether due to genetic, infectious or environmental factors. We believe that the evolution of disease in patients and research to elucidate the relationship between social science and environmental are pertinent contemporaneous subjects. [ABSTRACT FROM AUTHOR]

Aims: Heterozygous alpha-1-antitrypsin (A1AT) Pi*MZ variant has been shown to increase the risk of developing liver cirrhosis in patients with non-alcoholic fatty liver disease (NAFLD). We aimed to determine the association between heterozygous Pi*MZ and Pi*MS variants and development of hepatic decompensation events in NAFLD patients., Methods: We included patients with NAFLD who also had A1AT genotyping performed from 2005 to 2020. We recorded demographic and clinical variables, and data on hepatic events (ascites, hepatic encephalopathy, esophageal variceal bleed, or hepatocellular carcinoma), if any. We performed binary logistic regression analysis to assess the association between A1AT variants and hepatic events, and calculated Odds ratio (OR) with their 95% confidence intervals (Cl)., Results: We included 1532 patients with NAFLD, of which 1249 patients had Pi*MM, 121 had Pi*MS, and 162 had Pi*MZ. Of the 1532 patients, hepatic events developed in 521 (34%) patients. The percentage of patients with Pi*MZ variant was significantly higher in patients with hepatic events as compared to patients without hepatic events (18.7 % vs 8.1%, p<0.0001). Pi*MZ variant was noted to significantly increase the odds of developing hepatic events in NAFLD patients, unadjusted OR: 1.82 (1.3-2.5, p<0.001), adjusted OR (for age, sex, body mass index, and diabetes mellitus) 1.76 (1.2-2.5, p = 0.002). Pi*MS variant did not increase the odds of hepatic events in NAFLD patients, OR: 0.92 (0.6-1.4, p = 0.70)., Conclusion: Patients with NAFLD and A1AT Pi*MZ variant are at increased risk for developing hepatic decompensation. NAFLD patients should be offered A1AT genotyping for risk stratification, counseling, and multidisciplinary intervention for NAFLD., Competing Interests: Disclosures Arvind Murali, Sameer Prakash, and Antonio Sanchez declare that they have no conflict of interest or other financial disclosures relevant to the subject matter. The study protocol was approved by the institutional review board., (Copyright © 2022 Elsevier Masson SAS. All rights reserved.)

Background: Alpha-1 antitrypsin (A1AT) is a protease inhibitor that protects the tissues from degradation by neutrophil elastase under certain pathological process. Alpha-1 antitrypsin deficiency (A1ATD) could associate with both lung and liver pathogenicities. Of all the deficiency alleles, Z mutant is the most common variant and causes severe complications. Here, we described a novel and quick method to detect Z mutant using the base-quenched probe technique in only one single PCR reaction. Methods: Primers and probe were designed based on the base-quenched probe technique. Two vectors, representing the two genotypes, were constructed as amplification templates for validating the method. The Z mutant (GAG342AAG) was analyzed according to the melting curve. Finally, the accuracy was confirmed by direct sequencing. Results: Z mutant could be accurately distinguished from the wild type. The wild type resulted in high melting temperature (TM) (48.64±1.33°C), while when the Z mutation was present, the TM was shifted to an obvious low TM (41.38±0.9017°C). The sensitivity reached a low of 103 copies of template DNA with a clear melting valley and a complete concordance occurred between this method and the direct DNA sequencing. Conclusion: The present described method is simple, quick and economic as well as suitable for large-scale genotyping studies and clinical testing of Z mutant in patients with emphysema and cirrhosis. [ABSTRACT FROM AUTHOR]

Alpha 1 -proteinase inhibitor (A1PI) augmentation is the only specific treatment targeting the underlying deficiency in alpha 1 -antitrypsin deficiency (AATD). The demonstration of efficacy has been based on maintaining the biochemical surrogate endpoints of plasma antigenic and functional A1PI levels above >11 μM. Here we report a biochemical comparability analysis based on data from a phase 2/3, randomized, double-blind, two-arm study with partial crossover of Glassia® (Baxalta US Inc. Westlake Village, CA, USA) and Prolastin® (Grifols Therapeutics LLC, Research Triangle Park, NC, USA) in patients with AATD (NCT00460096). Patients (N = 50) were randomly assigned in a 2:1 ratio to receive either Glassia (n = 33) or Prolastin (n = 17), respectively. In the present study, data from patients in the per-protocol population (n = 29, Glassia; n = 12, Prolastin) were analyzed. We compared the biochemical efficacy of these two A1PI products at steady state of A1PI in plasma after weekly intravenous administration of A1PI at a dose of 60 mg/kg body weight. For both antigenic and functional A1PI levels, with or without baseline correction, the geometric mean ratios (GMRs) of plasma trough levels (Glassia/Prolastin) over a 6-week period at steady state (Weeks 7–12 post-randomization) were near or above 100%, with the 90% confidence intervals (CIs) contained within the 80%–125% interval. For antigenic A1PI, the GMR (90% CI) was 115.8% (108.1–124.2) for baseline corrected and 114.2% (109.2–119.5) for uncorrected concentrations. For functional A1PI, the GMR (90% CI) was 98.7 (92.5–105.4) for baseline corrected and 107.8% (102.3–113.5) for uncorrected concentrations. In conclusion, the biochemical efficacy of Glassia using the endpoints of plasma antigenic and functional A1PI trough concentrations at steady state was comparable with Prolastin in patients with AATD. [ABSTRACT FROM AUTHOR]

Objective: Alpha1-antitrypsin deficiency (A1ATD) is the most important indication for liver transplantation in children. The gene frequencies vary in different ethnic groups. In the present study, we attempt to determine the frequencies of the most common defective alleles, Z and S, in Iranian children suffering from idiopathic neonatal cholestasis. Eighty-seven infants were typed for Z and S alleles. Methods: In a single center study, 87 consecutive liver biopsies from infants with cholestasis were reviewed and patients with neonatal cholestasis enrolled in the study and cases with confirmed biliary tract atresia excluded. Formalin fixed paraffin embedded blocks were used for DNA extraction. AAT genotype was determined by polymerase chain reaction (PCR) assay and amplification of the two most common deficiency variants, S and Z alleles, and then sequencing of PCR products. Findings: There were 48 (55.2%) males and 39 (44.8%) females, with a median age of 60 days. Out of 87 of the study subject, 2 (2.2%) were heterozygous for the S allele, and no ZZ, SS or MZ individual was found in the patients. No other polymorphism was found in the sequencing results. Conclusion: In comparison to other populations, AAT deficiency seems not to be an important etiologic factor for neonatal cholestatic liver disease in Iran; however, further studies are recommended to estimate the true mutant gene frequencies. [ABSTRACT FROM AUTHOR]

Alpha1-antitrypsin deficiency, one of the three most common potentially lethal genetic disorders among whites, an autosomal recessive genetic disease, leads to early-onset panacinar emphysema, increased lung cancer risk, chronic liver disease and skin disorders. It has recently been studied the causal relationship of alpha1- antitrypsin deficiency (mainly the Z allele) to inflammatory bowel disease, but also to the increased incidence of extraintestinal manifestation, the most frequent being the cutaneous, articular and hepatic ones, as well as its relation to fibromyalgia. [ABSTRACT FROM AUTHOR]

Background: Hereditary hemochromatosis (HH) has an increased risk of hepatocellular cancer (HCC) both due to genetic risks and iron overload as iron overload can be carcinogenic; HH impacts the increasing risk of HCC, not only through the development of cirrhosis but concerning hepatic iron deposition, which has been studied further recently., Aim: To evaluate HH yearly trends, patient demographics, symptoms, comorbidities, and hospital outcomes. The secondary aim sheds light on the risk of iron overload for developing HCC in HH patients, independent of liver cirrhosis complications. The study investigated HH (without cirrhosis) as an independent risk factor for HCC., Methods: We analyzed data from National Inpatient Sample (NIS) Database, the largest national inpatient data collection in the United States, and selected HH and HCC cohorts. HH was first defined in 2011 International Classification of Disease - 9 th edition (ICD-9) as a separate diagnosis; the HH cohort is extracted from January 2011 to December 2019 using 275.01 (ICD-9) and E83.110 (ICD-10) diagnosis codes of HH. Patients were excluded from the HH cohort if they had a primary or secondary diagnostic code of cirrhosis (alcoholic, non-alcoholic, and biliary), viral hepatitis, alcoholic liver disease, non-alcoholic fatty liver disease (NAFLD), and non-alcoholic steatohepatitis (NASH). We removed these patients from the HH cohort to rule out bias or ICD-10 diagnostic errors. The HCC cohort is selected from January 2011 to December 2019 using the ICD-9 and ICD-10 codes of HCC. We selected a non-HCC cohort with the 1:1 fixed ratio nearest neighbor (greedy) propensity score method using the patients' age, gender, and race. We performed multivariate analysis for the risk factors of HCC in the HCC and non-HCC matched cohort. We further analyzed HH without cirrhosis (removing HH patients with a diagnosis of cirrhosis) as an independent risk factor of HCC after adjusting all known risk factors of HCC in the multivariate model., Results: During the 2011-2019 period, a total of 18031 hospitalizations with a primary or secondary diagnosis of HH (excluding liver diseases) were recorded in the NIS database. We analyzed different patients' characteristics, and we found increments in inpatient population trend with a Ptrend < 0.001 and total hospital cost of care trend from $42957 in 2011 to $66152 in 2019 with a Ptrend < 0.001 despite no change in Length of Stay over the last decade. The multivariate analyses showed that HH without cirrhosis (aOR, 28.8; 95%CI, 10.4-80.1; P < 0.0001), biliary cirrhosis (aOR, 19.3; 95%CI, 13.4-27.6; P < 0.0001), non-alcoholic cirrhosis (aOR, 17.4; 95%CI, 16.5-18.4; P < 0.0001), alcoholic cirrhosis (aOR, 16.9; 95%CI, 15.9-17.9; P < 0.0001), hepatitis B (aOR, 12.1; 95%CI, 10.85-13.60; P < 0.0001), hepatitis C (aOR, 8.58; 95%CI, 8.20-8.98; P < 0.0001), Wilson disease (aOR, 4.27; 95%CI, 1.18-15.41; P < 0.0001), NAFLD or NASH (aOR, 2.96; 95%CI, 2.73-3.20; P < 0.0001), alpha1-antitrypsin deficiency (aOR, 2.10; 95%CI, 1.21-3.64; P < 0.0001), diabetes mellitus without chronic complications (aOR, 1.17; 95%CI, 1.13-1.21; P < 0.0001), and blood transfusion (aOR, 1.80; 95%CI, 1.69-1.92; P < 0.0001) are independent risk factor for liver cancer., Conclusion: Our study showed an increasing trend of in-hospital admissions of HH patients in the last decade. These trends were likely related to advances in diagnostic approach, which can lead to increased hospital utilization and cost increments. Still, the length of stay remained the same, likely due to a big part of management being done in outpatient settings. Another vital part of our study is the significant result that HH without cirrhosis is an independent risk factor for HCC with adjusting all known risk factors. More prospective and retrospective large studies are needed to re-evaluate the HH independent risk in developing HCC., Competing Interests: Conflict-of-interest statement: All authors declare no conflict of interests for this article., (©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objective. Severe (PiZZ) alpha1-antitrypsin (AAT) deficiency is a risk factor for liver disease, i.e. juvenile cirrhosis in infancy, and cirrhosis and hepatoma in adulthood. Little is known about the risk of liver disease in individuals with moderate (PiSZ) AAT deficiency. To investigate the natural course of AAT deficiency, a cohort of PiZZ and PiSZ individuals identified by the Swedish National neonatal screening programme in 1972--74 is followed regularly. The aim of this study was to compare liver function in this cohort with healthy control subjects aged 30 years. Material and methods. Blood samples were obtained from 89 PiZZ, 40 PiSZ, and 84 control subjects (PiMM), and plasma levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and γγ-glutamyl (GT) transpeptidase were analysed. Results. The mean values of all liver enzymes were within the normal range in all Pi subgroups. However, the mean AST was higher in the PiZZ and PiSZ subgroups than in the PiMM subgroup ( p < 0.001), and the mean ALT was higher in the PiZZ individuals than in the controls ( p < 0.05), while GT did not differ significantly among the Pi subgroups. The PiZZ women taking oral contraceptives had higher mean AST and ALT ( p < 0.01) and GT ( p < 0.05) than the control women taking oral contraceptives. Conclusions. At the age of 30 years, PiZZ and PiSZ individuals have normal plasma levels of the transaminases AST and ALT, although they are significantly higher than those in healthy control subjects. Use of oral contraceptives seems to influence liver enzymes in PiZZ women. [ABSTRACT FROM AUTHOR]

The clinical characterization of a null variant of SERPINA1 – PiQ0 Heidelberg – resulting in alpha1-antitrypsin (AAT) deficiency is described. This rare mutation (c.-5+5 G > A) has been previously identified but not clinically described. The 77 year-old female patient had GOLD-3, Group B COPD, severe destructive panlobular emphysema and newly observed respiratory failure on exertion at the time the genetic analysis was performed. Serum AAT level was 0.1 g/L (reference 0.9–2.0 g/L). Isoelectric focusing showed only the Z-protein indicating that this was a null mutation. The patient has started AAT replacement. Early screening and identification of AAT deficiency would allow for earlier intervention. [ABSTRACT FROM AUTHOR]

Summary: Background: Alpha1-antitrypsin (AAT) deficiency is an under-diagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The objective of the present screening was to estimate the AAT gene frequency and prevalence and to identify AAT deficiency cases in a large cohort of Lithuanian patients with COPD. Methods: A nationwide program of AAT deficiency was conducted in 1167 COPD patients, defined according to the GOLD criteria. Patients were collected from outpatient clinics in five different Lithuanian regions (Kaunas, Vilnius, Siauliai, Klaipeda and Alytus). AAT serum concentrations were measured by nephelometry; PI-phenotypes characterized by isoelectric-focusing. Results: Mean age and FEV1 were 62.0 (10.3) and 54.7% (10.9), respectively. Ninety-one AAT deficiency genotypes (40 MZ, 39 MS, 1 SS, 3 SZ and 8 ZZ) were identified. Calculated PI∗S and PI∗Z frequencies, expressed in per 1000, were 18.8 (95% CI: 13.9–25) and 25.3 (95% CI: 19.4–32.7), respectively. The calculated AAT gene prevalence (Hardy–Weinberg principle) was: 1/1.09 for MM, 1/28 for MS, 1/2814 for SS, 1/20 for MZ, 1/1049 for SZ and 1/1565 for ZZ. Calculated Odds ratio (OR) for PI∗Z in COPD vs. Lithuanian healthy people was of 1.87 (P =0.004). Conclusion: The OR for each genotypic class demonstrated a significant increase of MZ, SZ and ZZ genotypes in COPD patients. The results of the present study, with a significant number of ZZ individuals detected, support the general concept of targeted screening for AAT deficiency in countries like Lithuania, with a large population of COPD patients and low awareness among care-givers about this genetic condition. [Copyright &y& Elsevier]

Summary: Aim: Severe alpha1-antitrypsin (AAT) deficiency is one of the most common genetic disorders in Caucasians. The aim of the present study was to assess an unbiased frequencies of PI*S and PI*Z alleles using genotyping of a representative sample from the general population of Poland. Methods: A random sample of age- and gender-stratified residents, aged 20 years or older, was drawn from the municipal directory of Kraków, Poland. The two most common deficiency alleles: PI*S and PI*Z were genotyped with qualitative real-time PCR using degenerative dual-labeled allele-specific fluorescent probes. Results: In the total population of 859 adult subjects (mean age: 49.5 years; range: 20–90), 28 heterozygotes MS, 18 heterozygotes MZ and one homozygote S were diagnosed. The frequency of PI*S allele was 17.5 (95% CI: 11.6–23.9) per 1000; and that of PI*Z was 10.5 (95% CI: 5.8–15.7) per 1000. Therefore, the estimated prevalence of inherited severe AAT deficiency (homozygotes Z) in Poland is 1/9110 (95% CI: 1/4057–1/29,727). Conclusions: In the whole population of Poland comprising 38 millions, one may expect of about 4189 (95% CI: 1284–9406) subjects with severe AAT deficiency. These numbers are high enough to consider genetic testing being introduced into a common clinical practice. [Copyright &y& Elsevier]

Summary: Introduction: Individuals with severe alpha-1-antitrypsin (AAT) deficiency have a well-known risk of developing emphysema but it is not known at which age the first symptoms occur and lung function declines. The aim of this study was to examine the prevalence of smoking, respiratory symptoms and lung function at the age of 30 in AAT-deficient individuals (PiZ and PiSZ) identified by neonatal screening. Material and methods: One hundred and seven PiZ, 45 PiSZ and 197 control subjects (PiMM) filled in a questionnaire regarding smoking habits and symptoms. Ninety PiZ, 40 PiSZ and 84 control subjects underwent spirometry including FEV1 and FVC. Results: Twenty-one percent of PiZ, 23% of PiSZ and 34% of PiMM subjects had smoked at some time (p<0.05). Sixty-five percent of PiZ, 55% of PiSZ and 35% of PiMM ever-smokers reported shortness of breath on exertion (p<0.05 PiZ vs PiMM). The mean FEV1 was 101% predicted (95% CI 98–104) in PiZ, 101% predicted (95% CI 97–106) in PiSZ, and 96% predicted (95% 93–98) in PiMM individuals (p<0.05). There was no difference in mean FEV1 when comparing ever- and neversmokers in the different Pi groups separately. Conclusion: At the age of 30, the AAT-deficient individuals in this cohort report more symptoms than the control subjects. Smoking is less common in the cohort compared to controls. Their lung function is normal. [Copyright &y& Elsevier]

Summary: Severe alpha1-antitrypsin (AAT) deficiency is an inherited disorder, leading to the development of emphysema in smokers at a relatively young age and disability in most smokers in their 40s. Panacinar emphysema is caused by damage to lung elastin and connective tissue as a result of smoking-induced release of neutrophil elastase in the lung, inadequately inhibited by the severe deficiency in AAT, the major inhibitor of neutrophil elastase. Severe antitrypsin deficiency (mostly protease inhibitor phenotype ZZ) is associated with retention of abnormal AAT in the liver, which may lead to neonatal hepatitis, liver disease in children, and liver disease and cirrhosis in adults. AAT replacement therapy by intravenous infusions of purified human AAT has been used to partially correct the biochemical defect and protect the lung against further injury, but has not yet been proven to be clinically effective in reducing the progression of disease in AAT-deficient patients. However, there was a suggestion of a slower progression of emphysema by chest computerized tomography in a small randomized trial, and non-randomized observational studies suggested a slower rate of decline in lung function in subjects with moderate airflow obstruction. AAT deficiency is often unrecognized. AAT testing is recommended in patients with chronic irreversible airflow obstruction with early onset of disease, those with disability in their 40s or 50s or positive family history, in immediate family members of AAT-deficient patients, in infants and children with liver disease, and adults with unexplained liver disease. [Copyright &y& Elsevier]