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

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

SUBMITTER: Santos G

PROVIDER: S-EPMC7886062 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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

Santos Gabriela G Turner Alice M AM

Faculty reviews 20201028

Clinical heterogeneity has been demonstrated in alpha-1 antitrypsin deficiency (AATD), such that clinical suspicion plays an important role in its diagnosis. The PiZZ genotype is the most common severe deficiency genotype and so tends to result in the worst clinical presentation, hence it has been the major focus of research. However, milder genotypes, especially PiSZ and PiMZ, are also linked to the development of lung and liver disease, mainly when unhealthy behaviors are present, such as smok ...[more]

PMID: 33659933

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Project description:Background: The diagnosis and clinical management of adults with alpha-1 antitrypsin deficiency (AATD) have been the subject of ongoing debate, ever since the publication of the first American Thoracic Society guideline statement in 1989.1 In 2003, the "American Thoracic Society (ATS)/European Respiratory Society (ERS) Statement: Standards for the Diagnosis and Management of Individuals with Alpha-1 Antitrypsin Deficiency" made a series of evidence-based recommendations, including a strong recommendation for broad-based diagnostic testing of all symptomatic adults with chronic obstructive pulmonary disease (COPD).2 Even so, AATD remains widely under-recognized. To update the 2003 systematic review and clinical guidance, the Alpha-1 Foundation sponsored a committee of experts to examine all relevant, recent literature in order to provide concise recommendations for the diagnosis and management of individuals with AATD. Purpose: To provide recommendations for: (1) the performance and interpretation of diagnostic testing for AATD, and (2) the current management of adults with AATD and its associated medical conditions. Methods: A systematic review addressing the most pressing questions asked by clinicians (clinician-centric) was performed to identify citations related to AATD that were published since the 2003 comprehensive review, specifically evaluating publications between January 2002 and December 2014. Important, more recent publications were solicited from the writing committee members as well. The combined comprehensive literature reviews of the 2003 document and this current review comprise the evidence upon which the committee's conclusions and recommendations are based. Results: Recommendations for the diagnosis and management of AATD were formulated by the committee. Conclusions: The major recommendations continue to endorse and reinforce the importance of testing for AATD in all adults with symptomatic fixed airflow obstruction, whether clinically labeled as COPD or asthma. Individuals with unexplained bronchiectasis or liver disease also should be tested. Family testing of first-degree relatives is currently the most efficient detection technique. In general, individuals with AATD and emphysema, bronchiectasis, and/or liver disease should be managed according to usual guidelines for these clinical conditions. In countries where intravenous augmentation therapy with purified pooled human plasma-derived alpha-1 antitrypsin is available, recent evidence now provides strong support for its use in appropriate individuals with lung disease due to AATD.

Project description:BACKGROUND:Alpha-1-antitrypsin (AAT) deficiency (AATD) of Z, Mmalton, Siiyama type is associated with liver storage of the mutant proteins and liver disease. The Z variant can be diagnosed on isoelectric focusing (IEF) while Mmalton and Siiyama may be missed or misdiagnosed with this technique. Therefore, molecular analysis is mandatory for their characterization. In particular, that holds true for the Mmalton variant as on IEF profile it resembles the wild M2 subtype. METHODS:This is a retrospective analysis involving review of medical records and of liver biopsy specimens from a series of Mmalton, Z and Siiyama Alpha-1-antitrypsin deficiency patients. The review has been implemented by additional histological stains, electron microscopic observations and 3-D modeling studies of the sites of the mutations. RESULTS:Z, Mmalton and Siiyama liver specimen contained characteristic intrahepatocytic PAS-D globules. The globules differed in the three variants as only Mmalton cases showed dark basophilic precipitates within the AAT inclusions. The precipitates were visualized in haematoxylin-eosin (H.E.) stained preparations and corresponded to calcium precipitates as demonstrated by von Kossa staining. On immunohistochemistry, ZAAT inclusions were stained by polyclonal as well as monoclonal noncommercial anti-AAT antibody (AZT11), whilst Mmalton and Siiyama inclusion bodies remained negative with the monoclonal anti-Z antibody. 3-D protein analysis allowed to predict more severe misfolding of the Mmalton molecule as compared to Z and Siiyama that could trigger anomalous interaction with endoplasmic reticulum chaperon proteins, namely calcium binding proteins. CONCLUSIONS:Mmalton AAT inclusion bodies contain calcium precipitates inside them that allow the differential diagnosis with Siiyama and ZAAT inclusions in routine histological sections. The study has confirmed the specificity of the monoclonal AZT11 for the Z mutant. Thus, the combination of these two features is crucial for the distinction between the three variants and for predicting the genotype, whose confirmation would definitely require molecular analysis. Our study provides new data on the pathomorphogenesis of Mmalton inclusion bodies whose mineralization could play a central role in disease pathogenesis of Mmalton that is distinct from the Z and Siiyama variants. Calcium is known to be a major effector of cell death either via the increased intracellular concentration or the alteration of homeostasis.

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

Publications

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

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