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Objectives Failure to produce sufficient quantities of functional α1-antitrypsin (AAT) can result in AAT deficiency (AATD) and significant comorbidities. Laboratory testing plays a vital role in AATD, with diagnosis requiring documentation of both a low AAT level and a mutated allele. This retrospective evaluation examines the efficacy of a liquid chromatography–tandem mass spectrometry (LC-MS/MS) (proteotyping)–based algorithm for AATD detection. Methods A 16-month retrospective data analysis was performed on two cohorts: 5,474 samples tested with the proteotype-based algorithm and 16,147 samples directly tested by isoelectric focusing (IEF) phenotyping. Results LC-MS/MS reduced the rate of IEF testing by 97%. The 3% of cases reflexed to IEF resulted in 12 (0.2%) additional phenotype findings. Retrospectively applying the proteotype-based algorithm to the IEF cohort demonstrated a 99.9% sensitivity for the detection of deficiency-associated phenotypes. Most deficiency phenotypes missed by the proteotyping algorithm would come from heterozygous patients with an F, I, or P paired to an S or Z. In all of these cases, patient AAT levels were greater than 70 mg/dL, above the threshold for AAT augmentation therapy. Conclusions The proteotype algorithm is a sensitive and cost-effective approach for the diagnosis of clinical AAT deficiency.

Background: The study of hematic concentrations of alpha1 antitrypsin (AAT) is currently one step in the diagnosis of AAT deficiency. To try to clarify the relevance of the laboratory techniques, we carried out a systematic review of the literature. Methods: Studies evaluating the quantification of AAT in peripheral blood were searched in PubMed in July 2021. The selection criteria included (1) any type of study design that included a quantification of AAT in peripheral blood; (2) studies written in English or Spanish; (3) studies evaluating human beings; and (4) studies involving adults. Results: Out of 207 studies, the most frequently used techniques were nephelometry (43.9%), followed by ELISA (19.8%) and turbidimetry (13.5%). Altogether, 182 (87.9%) cases expressed their results in units of gram, while 16 (7.7%) articles expressed them in units of mole. Only 2.9% articles referred to the standard used, 43.5% articles indicated the commercial kit used, and 36.2% indicated the analyzer used. Conclusions: The technical aspects of these determinations are not always reported in the literature. Journals should be attentive to these technical requirements and ensure that they are included in the works in which AAT is determined in order to ensure a correct interpretation of the study findings.

α-1 Antitrypsin (AAT) deficiency is the leading genetic cause of emphysema; however, until recently, no genuine animal models of AAT deficiency existed, hampering the development of new therapies. This shortcoming is now addressed by both AAT-null and antisense oligonucleotide mouse models. The goal of this study was to more fully characterize the antisense oligonucleotide model. Both liver AAT mRNA and serum AAT levels were lower in anti-AAT versus control oligonucleotide-treated mice after 6, 12, and 24 wk. Six and twelve weeks of anti-AAT oligonucleotide therapy induced emphysema that was worse in female than male mice: mean linear intercept 73.4 versus 62.5 μm ( P = 0.000003). However, at 24 wk of treatment, control oligonucleotide-treated mice also developed emphysema. After 6 wk of therapy, anti-AAT male and female mice demonstrated a similar reduction serum AAT levels, and there were no sex or treatment-specific alterations in inflammatory, serine protease, or matrix metalloproteinase mRNAs, with the exception of chymotrypsin-like elastase 1 ( Cela1), which was 7- and 9-fold higher in anti-AAT versus control male and female lungs, respectively, and 1.6-fold higher in female versus male anti-AAT-treated lungs ( P = 0.04). While lung AAT protein levels were reduced in anti-AAT-treated mice, lung AAT mRNA levels were unaffected. These findings are consistent with increased emphysema susceptibility of female patients with AAT-deficiency. The anti-AAT oligonucleotide model of AAT deficiency is useful for compartment-specific, in vivo molecular biology, and sex-specific studies of AAT-deficient emphysema, but it should be used with caution in studies longer than 12-wk duration.

Importance: Alpha1-antitrypsin (AAT) deficiency is a common, but an underdiagnosed genetic condition, affecting 1 in 1500 individuals. It can present insidiously with liver disease in children. Although clinical practice guidelines exist for the management of AAT deficiency, especially with regards to pulmonary involvement, there are no published recommendations that specifically relate to the management of the liver disease and monitoring for lung disease associated with this condition, particularly in children. Objective: To review the literature on the management of AAT deficiency-associated liver disease in adults and children. Evidence Review: A systematic search for articles indexed in PubMed and published was undertaken. Some earlier selected landmark references were included in the review. Search terms included: "alpha1-antitrypsin deficiency"; "liver disease"; "end-stage liver disease"; "liver transplantation" and "preventative management". Recommendations for the management of children with suspected or confirmed AAT deficiency were made according to the Strength of Recommendation Taxonomy scale. Findings: Liver complications arising from AAT deficiency result from the accumulation of mutated AAT protein within hepatocytes. Liver disease occurs in 10% of children, manifested by cholestasis, pruritus, poor feeding, hepatomegaly, and splenomegaly, but the presentation is highly variable. A diagnostic test for AAT deficiency is recommended for these children. Baseline liver function tests should be obtained to assess for liver involvement; however, the only curative treatment for AAT deficiency-associated liver disease is organ transplantation. Conclusion and Relevance: There should be a greater vigilance for AAT deficiency testing among pediatricians. Diagnosis should prompt assessment of liver involvement. Children with AATdeficiency- associated liver disease should be referred to a liver specialist and monitored throughout their lifetimes for the symptoms of AAT-deficiency-related pulmonary involvement.

As NPs play an increasingly vital role in primary care, they must be well versed in a variety of conditions. Alpha-1 antitrypsin (AAT) deficiency is a respiratory disease for which there is particularly low awareness in both the nursing profession and the wider medical community. This article provides an overview of AAT deficiency and includes guidance for diagnosing the disease.

Intravenous infusion of alpha-1 antitrypsin (AAT) was approved by the United States Food and Drug Administration (FDA) to treat emphysema associated with AAT deficiency (AATD) in 1987 and there are now several FDA-approved therapy products on the market, all of which are derived from pooled human plasma. Intravenous AAT therapy has proven clinical efficacy in slowing the decline of lung function associated with AATD progression; however, it is only recommended for individuals with the most severe forms of AATD as there is a lack of evidence that this treatment is effective in treating wild-type heterozygotes (e.g., PI*MS and PI*MZ genotypes), for which the prevalence may be much higher than previously thought. There are large numbers of individuals that are currently left untreated despite displaying symptoms of AATD. Furthermore, not all countries offer AAT augmentation therapy due to its expense and inconvenience for patients. More cost-effective treatments are now being sought that show efficacy for less severe forms of AATD and many new therapeutic technologies are being investigated, such as gene repair and other interference strategies, as well as the use of chemical chaperones. New sources of AAT are also being investigated to ensure there are enough supplies to meet future demand, and new methods of assessing response to treatment are being evaluated. There is currently extensive research into AATD and its treatment, and this chapter aims to highlight important emerging treatment strategies that aim to improve the lives of patients with AATD.

The elderly and patients with several comorbidities experience more severe cases of coronavirus disease 2019 (COVID-19) than healthy patients without underlying medical conditions. However, it is unclear why these people are prone to developing alveolar pneumonia, rapid exacerbations, and death. Therefore, we hypothesized that people with comorbidities may have a genetic predisposition that makes them more vulnerable to various factors; for example, they are likely to become more severely ill when infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). To test this hypothesis, we searched the literature extensively. Polymorphisms of genes, such as those that encode angiotensin-converting enzyme 1 (ACE1), have been associated with numerous comorbidities, such as cardiovascular disease, hypertension, diabetes, chronic kidney disease, and obesity, and there are potential mechanisms to explain these associations (e.g., DD-type carriers have greater ACE1 activity, and patients with a genetic alpha-1 anti-trypsin (AAT) deficiency lack control over inflammatory mediators). Since comorbidities are associated with chronic inflammation and are closely related to the renin–angiotensin–aldosterone system (RAAS), these individuals may already have a mild ACE1/ACE2 imbalance before viral infection, which increases their risk for developing severe cases of COVID-19. However, there is still much debate about the association between ACE1 D/I polymorphism and comorbidities. The best explanation for this discrepancy could be that the D allele and DD subtypes are associated with comorbidities, but the DD genotype alone does not have an exceptionally large effect. This is also expected since the ACE1 D/I polymorphism is only an intron marker. We also discuss how polymorphisms of AAT and other genes are involved in comorbidities and the severity of SARS-CoV-2 infection. Presumably, a combination of multiple genes and non-genetic factors is involved in the establishment of comorbidities and aggravation of COVID-19.

Among 68 countries in the world, severity of the COVID-19 epidemic was correlated with the prevalence of α-1 antitrypsin (AAT) deficiency. For the severe variant, PI*Z, the correlation coefficient (CC) was 0.8584 for the number of patients and 0.8713 for the number of deaths. For the milder variant, PI*S, it was 0.5818 and 0.6326, respectively. In Japan, the number of patients and deaths correlated with the population size with a CC of 0.6667 and 0.7074 respectively, and was proportional to the population size to the power of 1.65 and 1.54. The prevalence of AAT deficiency also correlated with the epidemiological pattern of COVID-19. In countries with high prevalence of AAT deficiency, after the initial rise, the daily number of patients and that of deaths ran parallel at a high level for more than 6 months without sign of abatement. In countries with a low prevalence of AAT deficiency, after the first wave of the epidemic, the number of the deaths decreased continuously while the number of patients remained the same or even increased resulting in a decreasing case-fatality rate. When the cumulative number of deaths was plotted on the y-axis against the cumulative number of patients on the x-axis, plots fell on a straight line in countries with a high prevalence of AAT deficiency; while in countries with a low prevalence of AAT deficiency, a break appeared, after which the plots fell on flatter slope indicating decreasing case-fatality rate. The observation suggests emergence of an attenuated variant in countries with a low prevalence of AAT deficiency.

Deficiència d'alfa-1 antitripsina; Genotip; Malaltia pulmonar Deficiencia de alfa-1 antitripsina; Genotipo; Enfermedad pulmonar Alpha-1 antitrypsin deficiency; Genotype; Pulmonary disease Alpha-1 antitrypsin deficiency (AATD) is a significantly under-diagnosed genetic condition caused by reduced levels and/or functionality of alpha-1 antitrypsin (AAT), predisposing individuals to lung, liver or other systemic diseases. The management of individuals with the PI*MZ genotype, characterized by mild or moderate AAT deficiency, is less clear than of those with the most common severe deficiency genotype (PI*ZZ). Recent genetic data suggest that the PI*MZ genotype may be significantly more prevalent than currently thought. The only specific treatment for lung disease associated with severe AATD is the intravenous infusion of AAT augmentation therapy, which has been shown to slow disease progression in PI*ZZ individuals. There is no specific evidence for the clinical benefit of AAT therapy in PI*MZ individuals, and the risk of emphysema development in this group remains controversial. As such, current guidelines do not support the use of AAT augmentation in PI*MZ individuals. Here, we discuss the limited data on the PI*MZ genotype and offer pro and con perspectives on pursuing an AAT-specific therapeutic strategy in PI*MZ individuals with lung disease. Ultimately, further research to demonstrate the safety, risk/benefit balance and efficacy of AAT therapy in PI*MZ individuals is needed. Medical writing assistance for this manuscript was funded by CSL Behring; the role of the funder was to support medical writing assistance only.

Introduction: Alpha-1 antitrpsin (AAT) deficiency is considered as a situation that should be evaluated for all of COPD patients at least once in their lives at guidelines. Although this information is known at theoretical level, this rule is not followed in our country and in many other countries. The aim of this study was to evaluate the AAT serum levels of COPD patients and the detected genetic mutations. Methods: Study was planned after the visit of the researcher to the AATD reference center in Barcelona. The sample consisted of COPD patients who applied to two different health institutions. Comparison of patients characteristics was made according to examination status and levels of serum AAT, also detected mutations were evaluated. Results: Totally 135 COPD patients were evaluated. Mean age of the study population was 63.4±11.2, with male dominance (96.6%). Among them 54.8% of them were examined for serum AAT levels. The comparison of AAT level tested and non-tested groups showed that AAT level tested group’s mean age was lower (p Conclusion: Detection of COPD patients for AAT deficiency is feasible and relevant for future directions.

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.

This article belongs to the Special Issue Rare Respiratory Diseases: A Personal and a Public Health Problem., Ever since the first studies, restoring proteinase imbalance in the lung has traditionally been considered as the main goal of alpha1 antitrypsin (AAT) replacement therapy. This strategy was therefore based on ensuring biochemical efficacy, identifying a protection threshold, and evaluating different dosage regimens. Subsequently, the publication of the results of the main clinical trials showing a decrease in the progression of pulmonary emphysema has led to a debate over a possible change in the main objective of treatment, from biochemical efficacy to clinical efficacy in terms of lung densitometry deterioration prevention. This new paradigm has produced a series controversies and unanswered questions which face clinicians managing AAT deficiency. In this review, the concepts that led to the approval of AAT replacement therapy are reviewed and discussed under a new prism of achieving clinical efficacy, with the reduction of lung deterioration as the main objective. Here, we propose the use of current knowledge and clinical experience to face existing challenges in different clinical scenarios, in order to help clinicians in decision-making, increase interest in the disease, and stimulate research in this field.

Background: The Z mutation in alpha-antitrypsin (AAT) results in formation of polymeric chains within hepatocytes, with consequent reduction of AAT plasma levels and predisposition to emphysema. A small fraction of Z AAT polymers is also present in the circulation and in tissues, where it further decreases AAT anti-protease activity and may exert pro-inflammatory functions, thus contributing to the pathogenesis of lung disease in AAT deficiency (AATD). As circulating polymers are mainly secreted by the liver, their concentration in the plasma may reflect the extent of polymer accumulation in hepatocytes and the severity of associated liver diseases. Objectives: Quantification of plasma AAT polymers is a relevant diagnostic and prognostic biomarker in AATD. As most diagnostic flowcharts are performed on dried blood spots (DBS), we have standardized a method for accurate quantification of AAT polymers on DBS. Methods: We collected DBS from 20 AATD patients (10 PI*MZ and 10 PI*ZZ) and quantified AAT polymers on DBS eluates by a sandwich ELISA based on the polymer-specific 2C1 mAb for capture and an HRP-conjugated anti-AAT polyclonal for detection. Heat-induced polymers of plasma purified AAT were used as standards. Results: Polymer concentrations determined on DBS from PI*MZ (0,2±0,1 mg/dL) and PI*ZZ (1.1±0,7 mg/dL) subjects were comparable to the levels measured on matched plasma samples. Conclusions: We developed an assay that determines AAT polymer concentrations in DBS specimens. This assay will give the opportunity to test a high number of cases for plasma polymer content and thereby to evaluate the correlation of this parameter with individual lung and liver clinical manifestations of AATD.

Alpha-1 antitrypsin (AAT) deficiency is a common inherited metabolic disorder caused by a point mutation in the SERPIN1A gene. A small portion of homozygous PI*ZZ individuals develop severe liver disease that requires liver transplantation. Posttransplant survival is excellent. The largest burden of advanced liver disease lies within the adult population rather than children. Evaluation of lung function in adults before transplant is essential because of the underlying risk for chronic obstructive pulmonary disease. Post-liver transplantation lung function should also be monitored for decline. Although uncommon, cases of simultaneous lung and liver transplant for AAT deficiency have been reported.

Introduction: Subjects affected by alpha-1 antitrypsin (AAT) deficiency are susceptible to develop both asthma and atopy, even if the link between these conditions and AAT deficiency has still to be defined. The aim of this study was to evaluate the relationship between SERPINA1 gene mutations linked with AAT deficiency and atopy in a sample of asthmatics. In addition, we evaluated the atopy characteristics, as related to the AAT deficiency, in a sample of atopic outpatients. Materials and Methods: We prospectively evaluated 55 asthmatic outpatients with and without atopy and 47 atopic outpatients with and without asthma with a serum concentration of AAT Results: In 25 out of 55 outpatients (45%), a gene mutation was demonstrated and 39 out of 55 (71%) were atopic. The percentage of the SERPINA1 gene mutations in asthmatics with atopy was significantly higher than that in non-atopic asthmatic patients (χ2= 6.5; p= 0.01). In this group, patients with gene mutations had higher values in RV/TLC ratio than those without (p=0.009). In the group of 47 atopic outpatients with and without asthma and gene mutations, the percentage with seasonal atopy was significantly higher in mutated ones (41% vs 10%, χ2= 5.4; p= 0.02). Conclusion: We showed that gene mutations linked to AAT deficiency are significantly associated to atopy in asthmatic patients. Furthermore, we provided evidence that gene mutations linked to AAT deficiency are associated to seasonal atopy.

More than seventy-five isotypes of α-1-antitrypsin (AAT) have been described. To assess risks associated with AAT deficiency, isotype identification is necessary. Isoelectric focusing (IEF) is traditionally used for isotype differentiation, however, IEF has limited scope since it is a manual procedure that is not suitable for automation, and antitrypsin variants must differ in net charge in order to be resolved. In comparison, mass spectrometric assays are easily automated and offer a more complete solution for characterization of proteins. To capitalize on these advantages, we have developed a qualitative top-down liquid chromatography–mass spectrometry (LC–MS) method for selective phenotyping of AAT. This technique requires no sample pretreatment, and has the potential for use in routine clinical diagnostics. We have validated our LC–MS results against both DNA sequencing and IEF. Thus far, this method has identified the AAT variants PLowell, S and Z, as well as unique fragments shared by different M alleles. Its high selectivity is indirectly illustrated by the detection of a variant carrying the amino acid substitution p.Ala308Ser, which cannot be visualized by IEF.

Chronic obstructive pulmonary disease (COPD) is caused by α1-antitrypsin deficiency (AATD) genetic susceptibility and exacerbated by infection. The current pilot study aimed at studying the combined effect of AATD and bacterial loads on the efficacy of COPD conventional pharmacotherapy. Fifty-nine subjects (29 controls and 30 COPD patients) were tested for genetic AATD and respiratory function. The bacterial loads were determined to the patients’ group who were then given a long acting beta-agonist and corticosteroid inhaler for 6months. Nineteen percent of the studied group were Pi∗MZ (heterozygote deficiency variant), Pi∗S (5%) (milder deficiency variant), Pi∗ZZ (10%) (the most common deficiency variant), and Pi∗Mmalton (2%) (very rare deficiency variant). The patients’ sputum contained from 0 to 8×108CFU/mL pathogenic bacteria. The forced vital capacity (FVC6) values of the AAT non-deficient group significantly improved after 3 and 6months. Patients lacking AATD and pathogenic bacteria showed significant improvement in forced expiratory volume (FEV1), FEV1/FVC6, FVC6, and 6min walk distance (6MWD) after 6months. However, patients with AATD and pathogenic bacteria showed only significant improvement in FEV1 and FEV1/FVC6. The findings of this pilot study highlight for the first time the role of the combined AATD and pathogenic bacterial loads on the efficacy of COPD treatment.

Objectives: α1-Antitrypsin (AAT) deficiency is a hereditary disorder due to defective production of the serine protease inhibitor, AAT, which can cause lung and liver diseases. Severity of disease depends particularly on the phenotypic representation of AAT variants in the patient. Methods: In this study, we present determination of seven common and nine rare variant phenotypes of AAT using pediatric samples collected in Texas Children’s Hospital to address the knowledge gap in the identification of rare variants. We tested 16 different AAT variants that had been stored in a –80 °C freezer over the years to add to the reference library of AAT variants. The gold-standard isoelectric focusing electrophoresis method was used for analysis and interpretation of AAT variants. Each variant was inspected visually by comparing multiple bands, unique to phenotypic identity, with a previously identified pattern. Results: Seven common M, S, and Z variants were identified as M1M1, M2M2, M1M2, MS, SS, SZ, and ZZ. Nine rare variants were identified as FM, FS, FZ, PM, XM, YM, IM, TS, and EP. These were interpreted independently and in a blinded manner by an experienced technologist and two clinical chemists from two different institutions. Conclusions: Our results add to the reference library to identify the rare variant phenotypes of AAT protein. This report will guide clinical laboratories for proper assessment of rare variants and in turn contribute to accurate diagnosis and management of AAT deficiency.

Identified as a circulating serine-protease inhibitor, the genetic deficiency of which predisposes to the development of lung emphysema, alpha1-antitrypsin (AAT) has recently been found to possess various anti-inflammatory and immunomodulatory activities outside the biochemical inhibition of serine-proteases. AAT is presently extracted from human plasma to supply life-long infusions to patients with genetic AAT deficiency. However, its newly appreciated functions point to extended therapeutic uses; these, alongside modified production attempts, represent a novel and dynamic niche of drug repurposing, set apart from addressing lung emphysema in AAT-deficient individuals.The review provides a comprehensive summary of patent-protected inventions in the field of novel clinical indications for AAT and innovations in AAT production.A molecule no longer patentable per se, presents with novel clinical applications; its mechanism still unfolding. While modified protein sequences are patentable and potentially superior, they are burdened by regulatory setbacks. Thus, recent approaches in the context of AAT appear in patents that describe combinations with other drugs, redefined clinical subclasses, and unique recombinant entities, carefully skirting saturated areas of AAT patentology. It will be fascinating to follow technologies and creative patenting as AAT navigates the trying trades of pharmaceutical industry towards an increasing lineup of unmet clinical needs.

The PiSZ genotype results in less severe deficiency of alpha-1 antitrypsin (AAT) than PiZZ. Less is known about phenotypic and prognostic features.We studied 699 PiZZ, 126 PiSZ and 316 PiMM patients. All AAT deficiency (AATD) patients were augmentation naive. PiSZ were compared with PiZZ patients for clinical phenotype at baseline including CT findings, smoke exposure, progression of lung disease and survival. Similarly, PiSZ patients diagnosed as a result of investigation for possible lung disease (lung index cases) were compared with PiMM. Multivariable analytical techniques and matching (PiSZ to PiZZ) were employed to account for demographic differences.Pack-years smoked and FEV1 exhibited a negative correlation in PiSZ and ZZ patients (both r=-0.43), with emphysema and COPD occurring more commonly in PiZZ patients at20 pack-year exposure. In multivariable analyses, PiSZ patients were less likely to have emphysema (p0.01) and had better survival than PiZZ (p=0.017), but lung function decline did not differ significantly. 42% of PiSZ patients had upper-zone-dominant emphysema on CT scan. Analyses of AAT level confirmed a critical threshold at 11 μM, particularly with regard to phenotypes classical of PiZZ AATD.Significant baseline differences suggested that PiSZ had presented earlier to health services than PiMM. Once this was accounted for, risk of emphysema did not differ between PiSZ and PiMM although survival was lower in PiMM patients (p0.01).PiSZ patients are less susceptible to cigarette smoke than PiZZ. The pattern of emphysema may be similar at diagnosis to usual COPD.

α1 Antitripsin deficiency (AAT) is an orphan respiratory disease. Genetic risk factors of chronic obstructive pulmonary disease (COPD) can cause AAT and primary emphysema of the lungs. AAT genotyping plays the key role for diagnosis. Early detection of AAT deficient phenotypes is crucial for prevention and treatment of COPD and slowing emphysema progression. A case of inherited AAT deficiency in a patient with deficient phenotype PiZZ is described in this article. A diagnostic algorithm for AAT is proposed.

The combination of alpha-1 antitrypsin (AAT) deficiency, ANCA-vasculitis, and aortic aneurysm has been rarely described in literature. We report an eventually fatal case in a 70-year-old patient who initially presented with giant cell arteritis and ANCA associated glomerulonephritis. Several years later, he presented with aortic dissection due to large vessel vasculitis, raising the suspicion of AAT deficiency, as two first-line relatives had chronic obstructive pulmonary disease, while they never smoked. This diagnosis was confirmed by AAT electrophoresis and immunohistochemistry on a temporal artery biopsy. Considering AAT deficiency in these cases might lead to a more timely diagnosis.

After the discovery of the alpha-1 antitrypsin (AAT) deficiency–related lung emphysema by Laurell and Ericksson in Malmo (Sweden) 52 years ago, it took nearly a decade to discover its relationship with liver cirrhosis and neutrophilic panniculitis. Almost 30 years ago (1987), the US Food and Drugs Administration (FDA) approved Prolastin (purified AAT obtained from pooled human serum) for augmentation therapy in patients with severe AAT deficiency, suffering from pulmonary emphysema. In the 1990s, systemic vasculitis was added to the initial list of AAT deficiency–related diseases, and since then powerful patients’ associations and registries were created worldwide with the aim of promoting research and facilitating the patients’ diagnosis and access to treatment of this genetic condition. In the last 15 years, a growing number of new AAT antiinflammatory and immunomodulatory properties have been identified, suggesting multiple potential indications for a number of diseases, both inside and outside of the context of AAT deficiency. Lately the most advanced lines of research have been implemented using this condition as a model with the ultimate goal of achieving a cure. This introductory chapter aims to be a general introduction to the basic aspects of the AAT deficiency and to briefly report its exciting exemplary history.

Deficiency of alpha-1 antitrypsin (AAT) is caused by mutations in the SERPINA1 gene that results in low concentrations of AAT in circulation. The low AAT concentration can result in uninhibited neutrophil elastase activity in the lung, leading to pulmonary tissue damage and lung disease. Clinical evaluation for possible AAT deficiency includes two critical components: measuring AAT concentration in serum and identification of AAT deficiency alleles. In this chapter the methods by which AAT concentration can be measured in the clinical laboratory are described. The two most common methodologies for AAT quantification employ immunometric techniques, specifically nephelometry and turbidimetry, which are both based on light scatter technology. The AAT in the patient sample is combined with an anti-AAT polyclonal antibody solution leading to polymer formation and a proportional amount of subsequent light scatter. Descriptions of each method are presented, and specifics of quality control and assay parameters are discussed. A special discussion focuses on interpretation of results in the context of the different AAT genetic phenotypes and in the context of patients with active inflammatory conditions. Emerging techniques for AAT quantitation by mass spectrometry are also described given that both AAT quantitation and allele identification can be performed on the same assay.

Alpha-1 antitrypsin (AAT) genotyping is useful to confirm the clinical diagnosis of AAT deficiency and determine the specific allelic variant. Genotyping is the reference standard procedure for identifying rare allelic variants and characterizing new variants. It is also useful when there is a discrepancy between the patients' AAT levels and their phenotypes. AAT genotype is determined by an allele-specific genotyping assay for the S, Z, and Mmalton variants and by exome sequencing.

Objectives α1-Antitrypsin (AAT) deficiency is associated with an increased risk for lung and liver disease. Identification of AAT deficiency as the underlying cause of these diseases is important in correct patient management. Methods AAT deficiency is commonly diagnosed by demonstrating low concentrations of AAT followed by genotype and/or phenotype testing. However, this algorithm may miss novel AAT phenotypes. Results We report two cases of AAT deficiency in two patients: a case of the novel phenotype PiISF, misclassified as PiII by phenotyping, and a case of the rare phenotype PiMmaltonZ misclassified as PiM2Z. Conclusions These cases highlight the importance of understanding the limitations of a commonly used diagnostic algorithm, use of further gene sequencing in applicable cases, and the potential for underdiagnosis of AAT deficiency in patients with chronic obstructive pulmonary disease.

Alpha1-antitrypsin (AAT) deficiency was first described in 1963 together with its associations with severe early-onset basal panacinar emphysema. The genetic defects leading to deficiency have been elucidated and the pathophysiologic processes, clinical variation in phenotype, and the role of genetic modifiers have been recognized. Strategies to increase plasma (and hence tissue) concentrations of AAT have been developed. The only recognized specific therapeutic strategy is regular infusions of the purified plasma protein, and evidence confirms its efficacy in protecting the lung (at least partially). Early detection and modification of lifestyle remains crucial to the management of AAT deficiency.

This review discusses alpha - 1 - antitripsin (AAT) deficiency that is a wide - spread autosomal - recessive monogenic enzymopathy related to PI gene mutations. The most serious injury related to AAT deficiency is primary emphysema. A role of AAT for normal growth and functioning of the lungs as well as for occurrence of various structural and functional disorders is reviewed in the articles. The authors' own findings about AAT deficiency prevalence in Russian population are also shown. Clinical features of AAT deficiency and diagnostic methods are described. Finally, a clinical report of primary pulmonary emphysema due to congenital AAT deficiency is demonstrated.

Alpha-1 antitrypsin deficiency (AAT) is a hereditary recessive autosomal disease caused by mutations in the AAT gene. This disease is characterized by abnormally low AAT concentrations in plasma, which, in its homozygote form, carries a high risk for the development of early pulmonary emphysema and liver damage. Since the end of the 1980s augmentation therapy with AAT from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has been demonstrated to be safe and weekly infusions of AAT have resulted in plasma AAT concentrations above those considered protective for the lungs. However, life-long weekly infusions are not well accepted by patients, therefore pharmacokinetic studies have been performed to try to individualize the therapeutic regimen in order to obtain adequate trough serum AAT levels with prolonged intervals of administration. Therapeutic regimens administered every two weeks appear to be safe and result in adequate trough serum concentrations, but less-frequent administrations result in trough levels below the target. Alpha-1-antitrypsin deficiency is largely unrecognized and underdiagnosed. The foundation of national and international registries is a valid strategy to increase awareness about the disease and collect information about the natural history of this deficiency. Furthermore, the identification of a large number of patients will allow the development of new clinical trials aimed at finding better treatments for this infrequent condition.

Purpose Alpha-1 antitrypsin (AAT) is a significant anti-protease, anti-inflammatory, and immune-regulating protein, which favors organ tolerance after transplantation. Genetic testing for diagnosis of AAT deficiency (AATD) in lung transplant candidates with COPD, and post-transplant replacement of AAT in patients with AATD varies widely among transplants centers. The objective of this survey was to assess the practices of international lung transplant (LTx) centers, pertaining to the testing for, and replacement of, AAT in patients with AATD. Methods We developed a web-based survey to investigate the testing and replacement of AAT in patients with AATD undergoing LTx. The survey was distributed to international LTx centers via the ISHLT Connect platform. Results Respondents consisted of 49 LTx specialists from 10 countries (74% North America, 24% Europe, and 2% Australia). Centers performing >40 transplants per year (considered high-volume) comprised 52% of the respondents. Among all LTx centers, 57% reported screening all patients with COPD for AATD. Screening rates were equal between North America and Europe (58%). Low-volume LTx centers screened for AATD at a much higher rate, compared to high-volume LTx centers (78% vs. 36%). Only 25% of LTx centers provided AAT replacement prior to, or following LTx in patients with known AATD. North America LTx centers replaced AAT (31%) more frequently than European LTx centers (9%). As with screening rates, more low-volume LTx centers provided AAT (35%), compared to high volume centers (16%). One-third of LTx centers reported that, at their respective centers, diagnosis of AATD was an exclusionary criteria for double LTx. Conclusion This is the first systematic survey of LTx centers’ approaches to AATD, with specific attention on testing and post-LTx replacement of AAT. Standards of practice vary widely among lung transplant centers. Low-volume LTx centers screened for AATD, and replaced AAT after LTx in patients with AATD, more frequently than high-volume centers.

By analysis of a case of discrepancy between serum alpha-1-antitrypsin (AAT) level and genotype for the most common defective alleles associated with AAT deficiency (PI*S and PI*Z), a patient carrying the allele PI*Q0ourem has been identified for the first time outside of Portugal. This null allele has been implicated in cases of severe pulmonary emphysema. After developing a clinical assay for detection of c.1130insT mutation, based on fluorescent probes (HybProbe®), another 4 carriers of PI*Q0ourem allele were identified among 43 patients with abnormally low serum AAT levels based on their genotypes for PI*S and PI*Z alleles. Since 4 out 5 cases are from the same locality (La Palma Island, Spain), it is advisable to conduct genetic analyses of affected families and, possibly, a focused population screening.

Alpha-1-antitrypsin (AAT) deficiency is a rare genetic disease caused by an abnormal production of the serine protease inhibitor AAT. Liver transplantation (LT) cures cirrhosis caused by AAT deficiency and restores the normal production of AAT. There are few reports on the post-LT outcomes of patients with AAT deficiency. The aim of this study was to determine the characteristics and outcomes of patients undergoing LT for AAT deficiency at 3 large transplant centers. All patients undergoing LT at these 3 transplant centers from 1987 to 2012 for AAT deficiency (ZZ or SZ phenotype) were included. The most recent 50 patients with the MZ phenotype were also included for comparison. Data were collected retrospectively from internal databases and medical records. Seventy-three patients (50 with the ZZ phenotype and 23 with the SZ phenotype)underwent LT. The mean age was 52.8 years, and the majority of the patients (75.6%) were men. Before LT, serum AAT levels were lower for the ZZ patients versus the SZ patients (28.3 versus 58.0 mg/dL, P < 0.001). More than 40% of the SZ patients had an additional liver disease, whereas 8% in the ZZ group and 90% in the MZ group did. Before LT, there was no significant difference in pulmonary function between the ZZ and SZ groups. Seventeen patients (all with ZZ phenotype)had pulmonary function tests performed before and after LT. The forced expiratory volume in 1 second (FEV1) continued to decline for the majority. The 1-, 3-, 5-, and 10-year post-LT survival rates were 86%, 83%, 80%, and 72%, respectively, for the ZZ patients and 91%, 86%, 79%, and 79%, respectively, for the SZ patients. In conclusion, survival after LT for patients with ZZ or SZ AAT deficiency is excellent. Despite the normalization of AAT levels after LT, FEV1 continues to decline unexpectedly after LT in some ZZ and SZ patients.

Summary Background Alpha 1 -antitrypsin (AAT) deficiency, although largely under-diagnosed, is the underlying cause of approximately 1% of COPD cases. Lack of awareness leads to long delays in diagnostic testing. Subsequently, lifestyle and treatment choices with potentially positive effects on prognosis may be postponed. Methods Data on the testing and diagnostic practices for AAT deficiency were derived from the University of Pavia, Italy, and the University of Marburg, Germany. In addition, a survey of physicians was undertaken to explore their awareness and attitudes toward AAT deficiency. Results In Pavia and Marburg, 125 and 729 patients, respectively, were identified with severe AAT deficiency between July 2006 and June 2011. The median time interval between the onset of symptoms and diagnosis was 6 years (interquartile range [IQR], 11; range, 0–40) and 7 years (IQR, 13; range, 0–73), respectively. Augmentation therapy was initiated almost immediately in Germany while treatment was delayed by 3 months in Italy (IQR, 5.25; range, 1–118). Survey data (Italy, n = 181; Germany, n = 180) revealed that pulmonologists had greater knowledge of AAT deficiency than internists and general practitioners, however, overall, only 18–25% of physicians tested all COPD patients. One-third of the respondents stated that they "sometimes" offered augmentation therapy to patients diagnosed with AAT deficiency. Conclusions Major obstacles to AAT deficiency testing are physicians' attitudes and lack of understanding of the condition. A greater adherence to the guidelines that recommend diagnostic testing of all COPD patients, coupled with simpler testing protocols, may decrease delays and positively impact patient outcomes.

I: Alpha1-antitrypsin (AAT) deficiency is a hereditary disease characterized by decreased serum concentration of AAT. In most countries there is no strict epidemiological data for AAT deficiency, so the worldwide prevalence is unknown. A: Evaluation and characterization of the population tested for AAT deficiency during 9 yrs (2006-2015) by a reference laboratory in Portugal. M: Data from patients whose samples (blood/plasma) were sent to IPATIMUP (private non-profit laboratory of public utility) was retrospectively analysed. R: 1684 patients were evaluated, 58.8% male and 59.6% ≥18yrs old. The average number of requests was 187.1/yr and came from Pulmonology 35.6%, Paediatrics 33.2%, General Practice 5.5% and 17.9% came from family screening. 25.4% patients were PI*MZ, 23.5% PI*MM, 15.5% PI*MS, 11.1% PI*SZ, 9.5% PI*ZZ, 0.4% PI*ZQ0 and 0.30% PI*Q0Q0. Different types of rare deficiency and null alleles were detected: PI*Mmalton (n=59), PI*Q0Ourem (n=28), PI*PIowell (n=21), PI*I (n=17), PI*Mwurzburg (n=6), PI*Mheerlen (n=6), PI*T (n=4), PI*Q0Madrid (n=2), PI*Zaugsburg (n=2) and PI*Q0Lisboa (n=1). The authors emphasize the identification of four alleles that have not been described yet: PI*PGaia, PI*Q0Oliveira do Douro, PI*Q0Vila Real and PI*SGaia identified in 2009, 2012, 2013 and 2015, respectively. C: A high detection of severe AAT deficiency was found, along with several number of rare and null alleles, some of which were not described yet. The existence of national reference laboratories, especially dedicated to the diagnosis of AAT deficiency, a national registry and guidelines will improve the detection rate, essential to the knowledge of the epidemiology, allowing early intervention.

Asthma and male infertility are common diseases that can occur in the same patient. In some cases they could have patho-physiological changes common to both diseases. Our patient was seen as a result of having an irritating cough with wheezing, mainly at night, for more than a month. Asthma was diagnosed, and he responded favourably to the treatment given. Upon being informed that he had been examined for infertility for 5 years, alpha-1 antitrypsin (AAT) levels were requested. These confirmed that he had a phenotype SZ AAT deficiency. These findings, together with some evidence published recently, suggested that there is a need to rule out AAT deficiency in males with asthma and infertility.

Background. AAT deficiency is not a rare disease, but one of the most common congenital disorders increasing susceptibility of individuals with this deficiency to both lung and liver disease as well as other several adverse health effects. Studies to develop accurate estimates of the magnitude of this genetic disorder in any given country is critical for the development of screening programs for detection, diagnosis, and treatment of those individuals and/or families at risk. In the present study, estimates of the prevalence of the two major deficiency alleles PI S and PI Z were estimated for 25 countries in the Caribbean and North, Central, and South America to supplement our previous studies on 69 countries worldwide. Method. Using data on the prevalence of the two most common deficiency alleles PI S and PIZ in the mother countries that provided the majority of immigrants to these 25 countries, as well as genetic epidemiological studies on various genetic subgroups indigenous to the Caribbean and North, Central and South America it was possible to develop new formulas to estimate the numbers in each of five phenotypic classes, namely PI MS, PI MZ, PI SS, PI SZ and PI ZZ for each country. Results. When these 25 countries were grouped into six different geographic regions, the present study demonstrated striking differences when comparisons were made in numeric tables, maps and figures. Highly significant numbers of individuals at risk for AAT Deficiency were found in both the European, Mestizo and Mulatto populations for most of the 25 countries studied in the Caribbean and North, Central and South America. Conclusions. Our studies demonstrated striking differences in the prevalence of both the PIS and PIZ alleles among these 25 countries in the Caribbean and North, Central and South America and significant numbers of individuals at risk for adverse health effects associated with AAT Deficiency in a given country. When these data are added to the results from our earlier studies on 69 countries, we now have data on AAT Deficiency in 94 of the 193 countries worldwide listed in the CIA FactBook.

Although much remains to be done, recent advances and the advent of new methodologies are promising and should yield increased understanding of the genetic and epigenetic mechanisms influencing the pathogenesis of COPD, both related and unrelated to severe AAT deficiency. Such understanding should ultimately be translated into novel approaches to prevent, diagnose, and treat COPD.

Since the end of the 1980s augmentation therapy with alpha-1 antitrypsin (AAT) from human plasma has been available for specific treatment of emphysema due to AAT deficiency. Intravenous augmentation therapy has demonstrated to be safe and weekly infusions of AAT have demonstrated to result in plasma AAT concentration above those considered protective for the lungs. Randomized, placebo-controlled clinical trials have confirmed a reduction in the decline in lung density in patients receiving augmentation therapy. This is the first example of an antiprotease effective in restoring the protease/antiprotease imbalance in the lungs and changing the natural history of congenital emphysema. On the basis of the results obtained with the long-term infusion of AAT, there is growing interest in the possible use of antiprotease treatment in patients with smokers COPD. However, no drugs are yet available to increase antiprotease protection of the lower airways of smokers.