2
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Bench to Bedside and Back: The Evolving Story of Alpha-1 Antitrypsin Deficiency

      editorial
      1 , 2
      American Journal of Respiratory Cell and Molecular Biology
      American Thoracic Society

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          More than half a century ago, Laurell and Eriksson, working in their clinical biochemistry laboratory, noted anomalous findings in some of the samples sent for serum protein electrophoresis. In a minority of electrophoreses, the alpha-1 protein band was faint to nonexistent. Such a finding might easily have been dismissed as population variance, but Laurell and Eriksson left the confines of the lab to determine the clinical phenotype associated with the anomaly they observed. In doing so, they described what we now recognize as alpha-1 antitrypsin deficiency (1). Individuals with markedly reduced serum levels of this protective glycoprotein were predisposed to develop severe emphysema early in life, often with little or no tobacco smoke exposure. The basal predominant, panlobular emphysema was distinctive. Moreover, there was a predilection for the development of cirrhosis. That this disorder was genetic was established early; much later, the most common severe variant was localized to an abnormality on the SERPINA1 gene. The initial family kindreds had what we now understand to be the most common genotype associated with a severe deficiency of alpha-1 antitrypsin, the ZZ genotype. These bench-to-bedside findings have been of great importance in several ways. Scientifically, they described the foundations of the protease/antiprotease theory of the of emphysema pathogenesis. Clinically, they described an illness that became one of the first examples of personalized medical care with specific targeted therapy to treat a specific abnormality. More than a quarter-century ago, Wewer and colleagues reported that the infusion of purified alpha-1 antitrypsin protein in a dosage of 60 mg per kilogram per week could restore and maintain serum levels to theoretically protective thresholds with infused protein detectable in BAL fluid (2). Later observational studies confirmed that the accelerated decline in lung function associated with the deficiency could be slowed by this treatment and, in those who are most obstructed, loss of life delayed (3, 4). More recently, randomized controlled trials have shown that lung structure, as measured by computed tomographic scan lung density estimates, is preserved by infusions (5). Although the treatment of alpha-1 antitrypsin deficiency liver disease has lagged, there is growing evidence that as well as supportive measures and transplantation, the use of chaperone proteins holds promise for reducing the impact of damage to the liver by the retention of alpha-1 antitrypsin polypeptides. Despite the long history of alpha-1 antitrypsin deficiency, its characteristic clinical phenotype, and the availability of therapy, the disorder remains underdiagnosed (6). Simple routine testing could remedy this, and the Global Initiative for Chronic Obstructive Lung Disease Strategy, for example, recommends routine testing of all newly diagnosed patients with chronic obstructive pulmonary disease (COPD) (7). However, testing for the disorder is potentially complex. Not all gene variants result in decreased serum levels of alpha-1 antitrypsin protein. Some variants produce measurable but dysfunctional serum proteins, the F variant being the foremost example (8). Thus, the concerned clinician must consider an array of potential testing strategies. Simplest and least expensive remains quantifying serum levels of alpha-1 antitrypsin protein. Costing only a few dollars per test, it is widely available and screens adequately for the most common of alpha-1 antitrypsin deficiency disorders. But serum level measurements are inadequate for carrier detection, may be transiently elevated during acute inflammatory events, and will not detect functionally abnormal variants. If serum levels are low or the clinician’s index of suspicion is high, serum protein may be phenotyped, the approach pioneered by Laurell and Eriksson. Although their technology has been updated or replaced, their legacy has included the nonstandard nomenclature for alpha-1 antitrypsin abnormalities reflecting the mobility of proteins in electrophoresis gels. Protein phenotyping has the potential to detect both known and novel variants but may fail to reveal complex abnormalities. Today, protein phenotyping is typically bypassed in favor of genetic testing, usually targeting the most common of deficiency and dysfunction variants Z, S, F, and I. This four-variant PCR panel will characterize the vast majority of important and known alpha-1 antitrypsin abnormalities, but if a novel abnormality is suspected, sequencing becomes necessary. When is a novel abnormality suspected? Such a possibility should be considered when there is a discrepancy between what is measured and what is expected. Such discordance should not be dismissed as random variability in test results until the possibility of a novel variant has been considered. In this issue of the Journal, Matamala and colleagues (pp. 444–451) describe two novel in cis variants of the SERPINA1 gene that modify the properties of the PI*S allele, increasing hepatocellular retention and decreasing secretion into the bloodstream. The result is production of a functional null variant in what by conventional testing appears to be unremarkable S variant findings, typically a mild deficiency variant with little risk of liver disease (9). Their elegant investigation of the problem was sparked by relatively mild discordance among clinical findings, serum alpha-1 antitrypsin quantification and genotype as revealed by targeted gene testing. One man with COPD had a serum alpha-1 antitrypsin level ∼20% to 25% lower than expected for what appeared to be SS genotype. Their analysis found one S variant and what they have termed an S+ variant (S+p.Tyr138Cys), a variant associated with null-like activity. This additional in cis abnormality modulates the otherwise innocuous S variant to produce null-like activity with reduction of serum levels by trapping polypeptides in the hepatocyte. Thus, this patient who might otherwise have been regarded as having tobacco-related COPD with an unrelated mild alpha-1 antitrypsin deficiency variant was more correctly identified as having an intermediate deficiency variant potentially treatable by augmentation therapy. A second patient suffering from liver disease with the same in cis variant was initially identified as having MS genotype until further investigation revealed the S+ variant, thereby accounting for lower-than-expected serum levels of alpha-1 antitrypsin and retention of alpha-1 antitrypsin polypeptides in the endoplasmic reticulum of hepatocytes. A third patient with pulmonary involvement but lower-than-expected serum level for genotype MS was found to have type MS+ genotype, the in cis variant in this example producing null-like activity differently (S+p.Pro391Thr). These novel findings have implications for all of us in the field of pulmonary medicine. At the bedside, we must be alert to discordant findings. Although few clinicians could trace out the testing pathways that led to these complex and novel variants, clinicians should recognize when simple serum levels are lower than anticipated. Such findings should not be dismissed without further investigation. Communicating directly with the testing lab may provide further insights and suggestions for testing. As sequencing becomes accessible for clinical purposes, we might expect further rare variants to be described in this way. At the bench, we would do well to emulate the initiatives of Laurell and Eriksson. Even half a century on, the story of alpha-1 antitrypsin deficiency remains incomplete, and one cannot help but wonder how many variations to the story remain untold.

          Related collections

          Most cited references7

          • Record: found
          • Abstract: found
          • Article: not found

          Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial.

          The efficacy of α1 proteinase inhibitor (A1PI) augmentation treatment for α1 antitrypsin deficiency has not been substantiated by a randomised, placebo-controlled trial. CT-measured lung density is a more sensitive measure of disease progression in α1 antitrypsin deficiency emphysema than spirometry is, so we aimed to assess the efficacy of augmentation treatment with this measure.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Replacement therapy for alpha 1-antitrypsin deficiency associated with emphysema.

            In patients with alpha 1-antitrypsin deficiency, the development of emphysema is believed to be caused by the unchecked action of proteases on lung tissue. We evaluated the feasibility, safety, and biochemical efficacy of intermittent infusions of alpha 1-antitrypsin in the treatment of patients with alpha 1-antitrypsin deficiency. Twenty-one patients were given 60 mg of active plasma-derived alpha 1-antitrypsin per kilogram of body weight, once a week for up to six months. After a steady state had been reached, the group had trough serum levels of alpha 1-antitrypsin of 126 +/- 1 mg per deciliter as compared with 30 +/- 1 mg per deciliter before treatment, and serum anti-neutrophil elastase capacities of 13.3 +/- 0.1 microM as compared with 5.4 +/- 0.1 microM. The alpha 1-antitrypsin level in the epithelial-lining fluid of the lungs was 0.46 +/- 0.16 microM before treatment, and the anti-neutrophil elastase capacity was 0.81 +/- 0.13 microM. Six days after infusion, alpha 1-antitrypsin levels (1.89 +/- 0.17 microM) and anti-neutrophil elastase capacities (1.65 +/- 0.13 microM) in the lining fluid were significantly increased (P less than 0.0001). Because of the chronicity of the disorder and the lack of sensitive measures of lung destruction, the clinical efficacy of this therapy could not be studied rigorously. No changes in lung function were observed in our patients over six months of treatment. The only important adverse reactions to the 507 infusions were four episodes of self-limited fever. This study demonstrates that infusions of alpha 1-antitrypsin derived from plasma are safe and can reverse the biochemical abnormalities in serum and lung fluid that characterize this disorder. Together with lifetime avoidance of cigarette smoking, replacement therapy with alpha 1-antitrypsin may be a logical approach to long-term medical treatment.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Survival and FEV1 decline in individuals with severe deficiency of alpha1-antitrypsin. The Alpha-1-Antitrypsin Deficiency Registry Study Group.

              (1998)
              Subjects >= 18 yr of age with serum alpha1-antitrypsin (alpha1-AT) levels = 6 mo after enrolling, age and baseline FEV1% predicted were significant predictors of mortality. Results also showed that those subjects receiving augmentation therapy had decreased mortality (risk ratio [RR] = 0.64, 95% CI: 0. 43 to 0.94, p = 0.02) as compared with those not receiving therapy. Among 927 subjects with two or more FEV1 measurements >= 1 yr apart, the mean FEV1 decline was 54 ml/yr, with more rapid decline in males, those aged 30 to 44 yr, current smokers, those with FEV1 35 to 79% predicted, and those who ever had a bronchodilator response. Among all subjects, FEV1 decline was not different between augmentation-therapy groups (p = 0.40). However, among subjects with a mean FEV1 35 to 49% predicted, FEV1 decline was significantly slower for subjects receiving than for those not receiving augmentation therapy (mean difference = 27 ml/yr, 95% CI: 3 to 51 ml/yr; p = 0.03). Because this was not a randomized trial, we cannot exclude the possibility that these differences may have been due to other factors for which we could not control.
                Bookmark

                Author and article information

                Journal
                Am J Respir Cell Mol Biol
                Am. J. Respir. Cell Mol. Biol
                ajrcmb
                American Journal of Respiratory Cell and Molecular Biology
                American Thoracic Society
                1044-1549
                1535-4989
                October 2020
                October 2020
                October 2020
                : 63
                : 4
                : 403-404
                Affiliations
                [ 1 ]Professor of Medicine, University of Toronto, Toronto, Canada

                and
                [ 2 ]Asthma and Airway Centre, University Health Network, Toronto, Canada
                Author information
                http://orcid.org/0000-0002-2498-9859
                Article
                2020-0243ED
                10.1165/rcmb.2020-0243ED
                7528917
                32716630
                5d390a18-2c09-4278-8acc-54007f545717
                Copyright © 2020 by the American Thoracic Society

                This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 ( http://creativecommons.org/licenses/by-nc-nd/4.0/). For commercial usage and reprints, please contact Diane Gern ( dgern@ 123456thoracic.org ).

                History
                Page count
                Figures: 0, Tables: 0, Pages: 2
                Categories
                Editorials

                Comments

                Comment on this article