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<meta name="robots" content="INDEX,FOLLOW,NOARCHIVE" /><meta name="citation_inbook_title" content="GeneReviews® [Internet]" /><meta name="citation_title" content="Alpha-1 Antitrypsin Deficiency" /><meta name="citation_publisher" content="University of Washington, Seattle" /><meta name="citation_date" content="2023/06/01" /><meta name="citation_author" content="James K Stoller" /><meta name="citation_author" content="Vera Hupertz" /><meta name="citation_author" content="Loutfi S Aboussouan" /><meta name="citation_pmid" content="20301692" /><meta name="citation_fulltext_html_url" content="https://www.ncbi.nlm.nih.gov/books/NBK1519/" /><meta name="citation_keywords" content="AAT Deficiency" /><meta name="citation_keywords" content="A1AT Deficiency" /><meta name="citation_keywords" content="AATD" /><meta name="citation_keywords" content="Alpha-1 Antiprotease Deficiency" /><meta name="citation_keywords" content="AAT Deficiency" /><meta name="citation_keywords" content="A1AT Deficiency" /><meta name="citation_keywords" content="AATD" /><meta name="citation_keywords" content="Alpha-1 Antiprotease Deficiency" /><meta name="citation_keywords" content="Alpha-1-antitrypsin" /><meta name="citation_keywords" content="SERPINA1" /><meta name="citation_keywords" content="Alpha-1 Antitrypsin Deficiency" /><link rel="schema.DC" href="http://purl.org/DC/elements/1.0/" /><meta name="DC.Title" content="Alpha-1 Antitrypsin Deficiency" /><meta name="DC.Type" content="Text" /><meta name="DC.Publisher" content="University of Washington, Seattle" /><meta name="DC.Contributor" content="James K Stoller" /><meta name="DC.Contributor" content="Vera Hupertz" /><meta name="DC.Contributor" content="Loutfi S Aboussouan" /><meta name="DC.Date" content="2023/06/01" /><meta name="DC.Identifier" content="https://www.ncbi.nlm.nih.gov/books/NBK1519/" /><meta name="description" content="Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. 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AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. 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<div class="pre-content"><div><div class="bk_prnt"><p class="small">NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.</p><p>Adam MP, Feldman J, Mirzaa GM, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. </p></div><div class="iconblock clearfix whole_rhythm no_top_margin bk_noprnt"><a class="img_link icnblk_img" title="All GeneReviews" href="/books/n/gene/"><img class="source-thumb" src="/corehtml/pmc/pmcgifs/bookshelf/thumbs/th-gene-lrg.png" alt="Cover of GeneReviews®" height="100px" width="80px" /></a><div class="icnblk_cntnt eight_col"><h2>GeneReviews<sup>®</sup> [Internet].</h2><a data-jig="ncbitoggler" href="#__NBK1519_dtls__">Show details</a><div style="display:none" class="ui-widget" id="__NBK1519_dtls__"><div>Adam MP, Feldman J, Mirzaa GM, et al., editors.</div><div>Seattle (WA): <a href="http://www.washington.edu" ref="pagearea=page-banner&amp;targetsite=external&amp;targetcat=link&amp;targettype=publisher">University of Washington, Seattle</a>; 1993-2025.</div></div><div class="half_rhythm"><ul class="inline_list"><li style="margin-right:1em"><a class="bk_cntns" href="/books/n/gene/">GeneReviews by Title</a></li></ul></div><div class="bk_noprnt"><form method="get" action="/books/n/gene/" id="bk_srch"><div class="bk_search"><label for="bk_term" class="offscreen_noflow">Search term</label><input type="text" title="Search GeneReviews" id="bk_term" name="term" value="" data-jig="ncbiclearbutton" /> <input type="submit" class="jig-ncbibutton" value="Search GeneReviews" submit="false" style="padding: 0.1em 0.4em;" /></div></form><div><ul class="inline_list"><li><a href="/books/n/gene/advanced/">GeneReviews Advanced Search</a></li><li style="margin-left:.5em"><a href="/books/n/gene/helpadvsearch/">Help</a></li></ul></div></div></div><div class="icnblk_cntnt two_col"><div class="pagination bk_noprnt"><a class="active page_link prev" href="/books/n/gene/thctd/" title="Previous page in this title">&lt; Prev</a><a class="active page_link next" href="/books/n/gene/a-mannosidosis/" title="Next page in this title">Next &gt;</a></div></div></div></div></div>
<div class="main-content lit-style" itemscope="itemscope" itemtype="http://schema.org/CreativeWork"><div class="meta-content fm-sec"><h1 id="_NBK1519_"><span class="title" itemprop="name">Alpha-1 Antitrypsin Deficiency</span></h1><div itemprop="alternativeHeadline" class="subtitle whole_rhythm">Synonyms: AAT Deficiency, A1AT Deficiency, AATD, Alpha-1 Antiprotease Deficiency</div><p class="contrib-group"><span itemprop="author">James K Stoller</span>, MD, MS, <span itemprop="author">Vera Hupertz</span>, MD, and <span itemprop="author">Loutfi S Aboussouan</span>, MD.</p><a data-jig="ncbitoggler" href="#__NBK1519_ai__" style="border:0;text-decoration:none">Author Information and Affiliations</a><div style="display:none" class="ui-widget" id="__NBK1519_ai__"><div class="contrib half_rhythm"><span itemprop="author">James K Stoller</span>, MD, MS<div class="affiliation small">Respiratory and Education Institutes<br />Cleveland Clinic<br />Cleveland, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.fcc@jellots" class="oemail">gro.fcc@jellots</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Vera Hupertz</span>, MD<div class="affiliation small">Pediatric Gastroenterology<br />Pediatric Institute<br />Cleveland Clinic<br />Cleveland, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.fcc@vtrepuh" class="oemail">gro.fcc@vtrepuh</a></div></div></div><div class="contrib half_rhythm"><span itemprop="author">Loutfi S Aboussouan</span>, MD<div class="affiliation small">Respiratory Institute<br />Cleveland Clinic<br />Cleveland, Ohio<div><span class="email-label">Email: </span><a href="mailto:dev@null" data-email="gro.fcc@lssuoba" class="oemail">gro.fcc@lssuoba</a></div></div></div></div><p class="small">Initial Posting: <span itemprop="datePublished">October 27, 2006</span>; Last Revision: <span itemprop="dateModified">June 1, 2023</span>.</p><p><em>Estimated reading time: 33 minutes</em></p></div><div class="jig-ncbiinpagenav body-content whole_rhythm" data-jigconfig="allHeadingLevels: ['h2'],smoothScroll: false" itemprop="text"><div id="alpha1-a.Summary" itemprop="description"><h2 id="_alpha1-a_Summary_">Summary</h2><div><h4 class="inline">Clinical characteristics.</h4><p>Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with chronic obstructive lung disease (emphysema and/or bronchiectasis), characteristically in individuals older than age 30 years. Individuals with AATD are also at increased risk for panniculitis (migratory, inflammatory, tender skin nodules which may ulcerate on legs and lower abdomen) and C-ANCA-positive vasculitis (granulomatosis with polyangiitis). Phenotypic expression varies within and between families. In adults, smoking is the major factor in accelerating the development of COPD; nonsmokers may have a normal life span, but can also develop lung and/or liver disease. Although reported, emphysema in children with AATD is extremely rare. AATD-associated liver disease, which is present in only a small portion of affected children, manifests as neonatal cholestasis. The incidence of liver disease increases with age. Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. The risk for hepatocellular carcinoma (HCC) is increased in individuals with AATD.</p></div><div><h4 class="inline">Diagnosis/testing.</h4><p>The diagnosis of AATD relies on demonstration of low serum concentration of alpha-1 antitrypsin (AAT) and either identification of <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants in <i>SERPINA1</i> or detection of a functionally deficient AAT protein variant by protease inhibitor (PI) typing. Note: The unconventional nomenclature of <i>SERPINA1</i> alleles is based on electrophoretic protein variants that were identified long before the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> (<i>SERPINA1)</i> was known. Alleles were named with the prefix PI* (protease inhibitor*) serving as an alias for the gene. Using this nomenclature, the most common (normal) <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is PI*M and the most common pathogenic allele is PI*Z.</p></div><div><h4 class="inline">Management.</h4><p><i>Treatment of manifestations:</i> COPD is treated with standard therapy. Augmentation therapy with periodic intravenous infusion of pooled human serum alpha-1 antitrypsin (AAT) is used in individuals who have established emphysema. Lung transplantation may be an appropriate option for individuals with end-stage lung disease. Liver transplantation is the definitive treatment for severe disease (will restore AAT levels). Dapsone or doxycycline therapy is used for panniculitis; if refractory to this, high-dose intravenous AAT augmentation therapy is indicated.</p><p><i>Surveillance:</i> Every six to 12 months: pulmonary function tests including spirometry with bronchodilators and diffusing capacity measurements; liver function tests, platelet count and liver ultrasound, elastography (e.g., FibroScan), magnetic resonance imaging.</p><p><i>Agents/circumstances to avoid:</i> Smoking (both active and passive); occupational exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes; excessive use of alcohol.</p><p><i>Evaluation of relatives at risk:</i> Evaluation of parents, older and younger sibs, and offspring of an individual with severe AATD in order to identify as early as possible those relatives who would benefit from institution of treatment and preventive measures.</p></div><div><h4 class="inline">Genetic counseling.</h4><p>AATD is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal/">autosomal</a> <a class="def" href="/books/n/gene/glossary/def-item/codominant/">codominant</a> manner. If both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for one <i>SERPINA1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (e.g., PI*MZ), each sib of an affected individual has a 25% chance of being affected (PI*ZZ), a 50% chance of being heterozygous (PI*MZ), and a 25% chance of inheriting neither of the pathogenic variants (PI*MM). In the less frequent instance in which one parent is <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> (PI*ZZ) and one parent is heterozygous (PI*MZ), the risk to each sib of being homozygous (PI*ZZ) is 50%. Unless an individual with AATD has children with an affected individual or a <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a>, offspring will be obligate heterozygotes for a pathogenic variant. (Risk of lung disease may be increased in heterozygous individuals depending on their environmental exposures such as smoking.) Heterozygote testing for at-risk family members and prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> are possible once the pathogenic <i>SERPINA1</i> variants have been identified in the family.</p></div></div><div id="alpha1-a.Diagnosis"><h2 id="_alpha1-a_Diagnosis_">Diagnosis</h2><div id="alpha1-a.Suggestive_Findings"><h3>Suggestive Findings</h3><p>Alpha-1 antitrypsin deficiency (AATD) should be suspected in individuals with evidence of:</p><ul><li class="half_rhythm"><div>Chronic obstructive pulmonary disease (i.e., emphysema, persistent airflow obstruction, chronic bronchitis, and/or bronchiectasis); AND/OR</div></li><li class="half_rhythm"><div>Any of the following:</div><ul><li class="half_rhythm"><div>Liver disease at any age, including obstructive jaundice in infancy</div></li><li class="half_rhythm"><div>C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis)</div></li><li class="half_rhythm"><div>Necrotizing panniculitis</div></li></ul></li></ul></div><div id="alpha1-a.Establishing_the_Diagnosis"><h3>Establishing the Diagnosis</h3><p>The diagnosis of AATD relies on <a href="#alpha1-a.Demonstration_of_Low_Serum_Conc">demonstration of low serum concentration of AAT</a> AND EITHER OF THE FOLLOWING:</p><ul><li class="half_rhythm"><div>
<a href="#alpha1-a.Identification_of_Biallelic_Pat">Identification of <i>SERPINA1</i> pathogenic variants</a>
</div></li><li class="half_rhythm"><div>
<a href="#alpha1-a.Detection_of_a_Functionally_Def">Detection of a functionally deficient AAT protein</a>
</div></li></ul><div id="alpha1-a.Demonstration_of_Low_Serum_Conc"><h4>Demonstration of Low Serum Concentration of the Protein Alpha-1 Antitrypsin (AAT)</h4><p>A variety of techniques have been used to measure serum AAT concentration; currently the most commonly used technique is nephelometry.</p><ul><li class="half_rhythm"><div>Normal serum levels are 20-53 &#x000b5;mol/L or approximately 100-220 mg/dL by nephelometry.</div></li><li class="half_rhythm"><div>Serum levels observed in AATD with lung disease are usually &#x0003c;57 mg/dL.</div></li></ul></div><div id="alpha1-a.Identification_of_Biallelic_Pat"><h4>Identification of Biallelic Pathogenic Variants in <i>SERPINA1</i></h4><p>Molecular genetic testing approaches can include a combination of <b><a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted testing</b> (single-gene testing, <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a>) and <b>comprehensive</b>
<b><a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (<a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a>, <a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a>, <a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a>) depending on the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>.</p><p>Gene-targeted testing requires that the clinician determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>(s) are likely involved, whereas <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing does not. Because the <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a> of AATD is broad, individuals with the distinctive findings described in <a href="#alpha1-a.Suggestive_Findings">Suggestive Findings</a> are likely to be diagnosed using gene-targeted testing (see <b>Option 1</b>), whereas those in whom the diagnosis of AATD has not been considered are more likely to be diagnosed using genomic testing (see <b>Option 2</b>).</p><p><b>Option 1.</b> When the phenotypic and laboratory findings suggest the diagnosis of AATD <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> approaches can include <b>single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing</b> or use of a <b><a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b>:</p><ul><li class="half_rhythm"><div class="half_rhythm"><b>Single-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> testing.</b> Targeted analysis for the common PI*Z, PI*S, PI*I, and PI*F alleles (see <a href="#alpha1-a.Molecular_Genetics">Molecular Genetics</a> for standard nomenclature) may be performed first.</div><div class="half_rhythm">Sequence analysis of <i>SERPINA1</i> detects other pathogenic variants such as small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants.</div><div class="half_rhythm">Note: Depending on the sequencing method used, single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a>, multiexon, or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications may not be detected. If only one or no variant is detected by the sequencing method used, the next step is to perform gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> to detect exon and whole-gene deletions or duplications.</div></li><li class="half_rhythm"><div class="half_rhythm"><b>A <a class="def" href="/books/n/gene/glossary/def-item/multigene-panel/">multigene panel</a></b> that includes <i>SERPINA1</i> and other genes of interest (see <a href="#alpha1-a.Differential_Diagnosis">Differential Diagnosis</a>) is most likely to identify the genetic cause of the condition while limiting identification of variants of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a> and pathogenic variants in genes that do not explain the underlying <a class="def" href="/books/n/gene/glossary/def-item/phenotype/">phenotype</a>. Note: (1) The genes included in the panel and the diagnostic <a class="def" href="/books/n/gene/glossary/def-item/sensitivity/">sensitivity</a> of the testing used for each <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> vary by laboratory and are likely to change over time. (2) Some multigene panels may include genes not associated with the condition discussed in this <i>GeneReview</i>. (3) In some laboratories, panel options may include a custom laboratory-designed panel and/or custom phenotype-focused <a class="def" href="/books/n/gene/glossary/def-item/exome/">exome</a> analysis that includes genes specified by the clinician. (4) Methods used in a panel may include <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>, <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>, and/or other non-sequencing-based tests. For this disorder a multigene panel that also includes deletion/duplication analysis is recommended (see <a href="/books/NBK1519/table/alpha1-a.T.molecular_genetic_testing_use/?report=objectonly" target="object" rid-ob="figobalpha1aTmoleculargenetictestinguse">Table 1</a>).</div><div class="half_rhythm">For an introduction to multigene panels click <a href="/books/n/gene/app5/#app5.Multigene_Panels">here</a>. More detailed information for clinicians ordering genetic tests can be found <a href="/books/n/gene/app5/#app5.Multigene_Panels_FAQs">here</a>.</div></li></ul><p><b>Option 2.</b> When the diagnosis of AATD is not considered because an individual has atypical phenotypic features, <b>comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing</b> (which does not require the clinician to determine which <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>[s] are likely involved) is the best option. <b>Exome sequencing</b> is the most commonly used genomic testing method; <b><a class="def" href="/books/n/gene/glossary/def-item/genome-sequencing/">genome sequencing</a></b> is also possible.</p><p>If <a class="def" href="/books/n/gene/glossary/def-item/exome-sequencing/">exome sequencing</a> is not diagnostic, <b><a class="def" href="/books/n/gene/glossary/def-item/exome-array/">exome array</a></b> (when clinically available) may be considered to detect (multi)<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications that cannot be detected by <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a>.</p><p>For an introduction to comprehensive <a class="def" href="/books/n/gene/glossary/def-item/genomic/">genomic</a> testing click <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing">here</a>. More detailed information for clinicians ordering genomic testing can be found <a href="/books/n/gene/app5/#app5.Comprehensive_Genomic_Testing_1">here</a>.</p><p>Note: The nomenclature of <i>SERPINA1</i> alleles is unconventional because it is based on electrophoretic protein variants that were identified long before the <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> (<i>SERPINA1</i>) was identified [<a class="bk_pop" href="#alpha1-a.REF.cox.1980.429">Cox et al 1980</a>]. Because this older nomenclature is well established in the literature, it is used in this <i>GeneReview</i>.</p><p><i>SERPINA1</i> alleles encoding the variant AAT proteins were named with the prefix PI* (protease inhibitor*) serving as an alias for <i>SERPINA1</i> (which had yet to be identified). The six <i>SERPINA1</i> alleles discussed here are the following. (See <a href="#alpha1-a.Molecular_Genetics">Molecular Genetics</a> for more details and information on other alleles.)</p><ul><li class="half_rhythm"><div><b>PI*M.</b> The most common <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> in all populations described to date. Some benign variants of the PI*M allele are designated M1, M2, M3, etc.</div></li><li class="half_rhythm"><div><b>PI*Z.</b> The most common pathogenic <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>, resulting in a quantitatively and functionally deficient AAT protein. Individuals <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for PI*Z (i.e., PI*ZZ) have severe alpha-1 antitrypsin deficiency (AATD).</div></li><li class="half_rhythm"><div><b>PI*S.</b> A pathogenic <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> resulting in a quantitatively and functionally deficient AAT. It is usually of clinical consequence only in the <a class="def" href="/books/n/gene/glossary/def-item/compound-heterozygous/">compound heterozygous</a> state with another pathogenic allele (e.g., PI*SZ) and when the serum AAT level is &#x0003c;57 mg/dL.</div></li><li class="half_rhythm"><div><b>PI*F.</b> A pathogenic <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> that is distinctive because the resulting protein is functionally impaired in binding neutrophil elastase but quantitatively normal</div></li><li class="half_rhythm"><div><b>PI*I.</b> An <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> that is associated with mild quantitative deficiency</div></li><li class="half_rhythm"><div><b>Null alleles (sometimes designated PI*QO).</b> Pathogenic alleles that result in either no <a class="def" href="/books/n/gene/glossary/def-item/mrna/">mRNA</a> product or no protein production</div></li></ul><div id="alpha1-a.T.molecular_genetic_testing_use" class="table"><h3><span class="label">Table 1. </span></h3><div class="caption"><p>Molecular Genetic Testing Used in AATD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.molecular_genetic_testing_use/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.molecular_genetic_testing_use_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Gene&#x000a0;<sup>1</sup></th><th id="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Method</th><th id="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Proportion of Pathogenic Variants&#x000a0;<sup>2</sup> Detectable by Method</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<i>SERPINA1</i>
</td><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Targeted analysis</td><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">95%&#x000a0;<sup>3</sup></td></tr><tr><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Sequence analysis&#x000a0;<sup>4</sup></td><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">&#x0003e;99%&#x000a0;<sup>5</sup></td></tr><tr><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a>&#x000a0;<sup>6</sup></td><td headers="hd_h_alpha1-a.T.molecular_genetic_testing_use_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Rare&#x000a0;<sup>7</sup></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt>1. </dt><dd><div id="alpha1-a.TF.1.1"><p class="no_margin">See <a href="/books/NBK1519/#alpha1-a.molgen.TA">Table A. Genes and Databases</a> for <a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> and protein.</p></div></dd><dt>2. </dt><dd><div id="alpha1-a.TF.1.2"><p class="no_margin">See <a href="#alpha1-a.Molecular_Genetics">Molecular Genetics</a> for information on variants detected in this <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>.</p></div></dd><dt>3. </dt><dd><div id="alpha1-a.TF.1.3"><p class="no_margin">Targeted analysis for pathogenic variants is typically specific for detecting the pathogenic alleles PI*Z and PI*S, which account for 95% of AATD [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.1997.394">McElvaney et al 1997</a>].</p></div></dd><dt>4. </dt><dd><div id="alpha1-a.TF.1.4"><p class="no_margin">Sequence analysis detects variants that are benign, <a class="def" href="/books/n/gene/glossary/def-item/likely-benign/">likely benign</a>, of <a class="def" href="/books/n/gene/glossary/def-item/uncertain-significance/">uncertain significance</a>, <a class="def" href="/books/n/gene/glossary/def-item/likely-pathogenic/">likely pathogenic</a>, or pathogenic. Variants may include small intragenic deletions/insertions and <a class="def" href="/books/n/gene/glossary/def-item/missense/">missense</a>, <a class="def" href="/books/n/gene/glossary/def-item/nonsense-variant/">nonsense</a>, and <a class="def" href="/books/n/gene/glossary/def-item/splice-site/">splice site</a> variants; typically, <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> or whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions/duplications are not detected. For issues to consider in interpretation of <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> results, click <a href="/books/n/gene/app2/">here</a>.</p></div></dd><dt>5. </dt><dd><div id="alpha1-a.TF.1.5"><p class="no_margin"><a class="bk_pop" href="#alpha1-a.REF.gooptu.2014.116">Gooptu et al [2014]</a>, <a class="bk_pop" href="#alpha1-a.REF.greene.2016.16051">Greene et al [2016]</a>, <a class="bk_pop" href="#alpha1-a.REF.hatipo_lu.2016.487">Hatipo&#x0011f;lu &#x00026; Stoller [2016]</a>, <a class="bk_pop" href="#alpha1-a.REF.matamala.2018.706">Matamala et al [2018]</a>, <a class="bk_pop" href="#alpha1-a.REF.renoux.2018.161">Renoux et al [2018]</a>, <a class="bk_pop" href="#alpha1-a.REF.strnad.2020.1443">Strnad et al [2020]</a></p></div></dd><dt>6. </dt><dd><div id="alpha1-a.TF.1.6"><p class="no_margin">Gene-targeted <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> detects intragenic deletions or duplications. Methods used may include a range of techniques such as <a class="def" href="/books/n/gene/glossary/def-item/quantitative-pcr/">quantitative PCR</a>, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and a <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a>-targeted microarray designed to detect single-<a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> deletions or duplications.</p></div></dd><dt>7. </dt><dd><div id="alpha1-a.TF.1.7"><p class="no_margin">Rare <a class="def" href="/books/n/gene/glossary/def-item/exon/">exon</a> and whole-<a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> deletions have been reported [<a class="bk_pop" href="#alpha1-a.REF.takahashi.1990.403">Takahashi &#x00026; Crystal 1990</a>, <a class="bk_pop" href="#alpha1-a.REF.poller.1991.522">Poller et al 1991</a>, <a class="bk_pop" href="#alpha1-a.REF.strnad.2020.1443">Strnad et al 2020</a>].</p></div></dd></dl></div></div></div></div><div id="alpha1-a.Detection_of_a_Functionally_Def"><h4>Detection of a Functionally Deficient AAT Protein Variant by Protease Inhibitor (PI) Typing</h4><p>PI typing is performed by polyacrylamide gel <a class="def" href="/books/n/gene/glossary/def-item/isoelectric-focusing/">isoelectric focusing</a> (IEF) electrophoresis of serum in a gradient between pH 4 and 5. Note: IEF is no longer in common use in clinical practice.</p><ul><li class="half_rhythm"><div>Electrophoretic AAT protein variants (<a class="def" href="/books/n/gene/glossary/def-item/isoforms/">isoforms</a>) are designated by letters based on their migration pattern. For example, the normal AAT protein (designated M) migrates in the middle of the isoelectric field. The abnormal AAT deficiency protein (designated Z) migrates most slowly. Other variants have been given additional alphabetic designations; some rare variants have been named by place of origin of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>.</div></li><li class="half_rhythm"><div>Because a range of AAT protein variants from normal to deficient can be observed in an IEF assay, a reference of 13 common and five rare AAT protein variants is used to identify the specific AAT protein [<a class="bk_pop" href="#alpha1-a.REF.greene.2013.184">Greene et al 2013</a>].</div></li><li class="half_rhythm"><div>The limitations of IEF include inability to interpret an atypical electrophoretic pattern resulting from rare AAT protein variants and absence of AAT protein resulting from a <i>SERPINA1</i> pathogenic <a class="def" href="/books/n/gene/glossary/def-item/null/">null</a> <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</div></li><li class="half_rhythm"><div>IEF, the biochemical gold standard test for establishing the diagnosis of AATD, may be less costly than <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a>.</div></li></ul><p>Though the optimal algorithm for laboratory testing is not well defined and recommendations in available guidelines differ [<a class="bk_pop" href="#alpha1-a.REF.attaway.2019.2089">Attaway et al 2019</a>], the guidelines for the diagnosis and management of AATD by the American Thoracic Society / European Respiratory Society include recommended indications for genetic testing for AATD [<a class="bk_pop" href="#alpha1-a.REF.american_thoracic_society_european_respiratory_society.2003.818">American Thoracic Society &#x00026; European Respiratory Society 2003</a>].</p><div id="alpha1-a.T.clinical_indications_for_gene" class="table"><h3><span class="label">Table 2. </span></h3><div class="caption"><p>Clinical Indications for Genetic Testing</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.clinical_indications_for_gene/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.clinical_indications_for_gene_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical Indication</th><th id="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Recommendation<br />for Testing</th><th id="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strength of<br />Recommendation</th><th id="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Quality of<br />Evidence</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Pulmonary</b>
</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">All persons w/COPD regardless of age or ethnicity</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strong</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">All persons w/unexplained bronchiectasis</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strong</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="3" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Extra-</b>
<br />
<b>pulmonary</b>
</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">All persons w/unexplained chronic liver disease</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strong</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">All persons w/necrotizing panniculitis</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strong</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">All persons w/GPA</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Yes</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strong</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Proband</b>
<br />
<b>trigger</b>
</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Adult sibs of persons w/any abnormal AATD-related <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a></td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Offer test &#x00026; <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a></td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Strong</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Moderate</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Parents/offspring/minor sibs/extended family of persons w/any abnormal AATD-related <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a></td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Offer test &#x00026; <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a></td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Weak</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Low</td></tr><tr><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Pediatric</b>
<br />
<b>patients</b>
</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Children who do not fit previous indications</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Not supported; consider parental testing instead.</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">&#x02013;</td><td headers="hd_h_alpha1-a.T.clinical_indications_for_gene_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">&#x02013;</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#alpha1-a.REF.sandhaus.2016.668">Sandhaus et al [2016]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis</p></div></dd></dl></div></div></div></div></div></div><div id="alpha1-a.Clinical_Characteristics"><h2 id="_alpha1-a_Clinical_Characteristics_">Clinical Characteristics</h2><div id="alpha1-a.Clinical_Description"><h3>Clinical Description</h3><p>Alpha-1 antitrypsin deficiency (AATD) can present with hepatic dysfunction in individuals from infancy to adulthood and with obstructive lung disease and/or bronchiectasis, characteristically in individuals older than age 30 years. Phenotypic expression varies within and between families.</p><p>The severity of AATD depends on the <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> and resultant serum alpha-1 antitrypsin (AAT) level. Individuals <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for severe deficiency alleles (i.e., PI*ZZ) have low serum AAT levels, placing them at increased risk for chronic obstructive pulmonary disease (COPD) (see <a href="/books/NBK1519/table/alpha1-a.T.relationship_of_aat_protein_v/?report=objectonly" target="object" rid-ob="figobalpha1aTrelationshipofaatproteinv">Table 4</a>). Individuals with alleles associated with intrahepatic inclusions (e.g., Z, M<sub>malton,</sub> S<sub>iiyama</sub>) are also at increased risk of developing liver disease.</p><p>Under-recognition of AATD often causes a long delay between first symptoms and initial diagnosis of AATD (i.e., 5-7 years) and many individuals report seeing multiple physicians before the diagnosis is first established. Diagnostic delay is associated with worsened clinical status at the time of initial diagnosis [<a class="bk_pop" href="#alpha1-a.REF.tejwani.2019.915">Tejwani et al 2019</a>].</p><p>To date, approximately 5,000-10,000 individuals in the United States have been identified with a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> in <i>SERPINA1</i> [<a class="bk_pop" href="#alpha1-a.REF.american_thoracic_society_european_respiratory_society.2003.818">American Thoracic Society &#x00026; European Respiratory Society 2003</a>, <a class="bk_pop" href="#alpha1-a.REF.strnad.2020.1443">Strnad et al 2020</a>]. The following description of the phenotypic features associated with this condition is based on these reports.</p><div id="alpha1-a.T.select_features_of_aatd" class="table"><h3><span class="label">Table 3. </span></h3><div class="caption"><p>Select Features of AATD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.select_features_of_aatd/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.select_features_of_aatd_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Feature</th><th id="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">% of Persons w/Feature</th><th id="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">COPD (emphysema, chronic bronchitis)</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">60%-80%</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">The pattern &#x00026; distribution of emphysema should not dissuade from considering the diagnosis of AATD.</td></tr><tr><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bronchiectasis</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~27%</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Bronchiectasis is present on CT chest in ~90% of those w/PI*ZZ &#x00026; clinically evident in ~27% [<a class="bk_pop" href="#alpha1-a.REF.parr.2007.1215">Parr et al 2007</a>].</td></tr><tr><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Neonatal cholestasis</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~11%</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">~65% will go on to have severe liver disease.</td></tr><tr><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Cirrhosis</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">12%-40%</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Liver disease may be subclinical.</td></tr><tr><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Panniculitis</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Uncommon</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May be present in AATD phenotypes not assoc w/lung disease</td></tr><tr><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">GPA</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Uncommon but associated</td><td headers="hd_h_alpha1-a.T.select_features_of_aatd_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Odds ratio for having an abnormal AAT <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> is ~11 in persons w/GPA [<a class="bk_pop" href="#alpha1-a.REF.mahr.2010.3760">Mahr et al 2010</a>].</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; GPA = granulomatosis with polyangiitis</p></div></dd></dl></div></div></div><div id="alpha1-a.Lung_Disease"><h4>Lung Disease</h4><p><b>Adult-onset lung disease.</b> Chronic obstructive pulmonary disease (COPD), specifically emphysema and/or chronic bronchitis, is the most common clinical manifestation of AATD. Bronchiectasis is also associated with AATD.</p><p>In adults, smoking is the major factor in accelerating the development of COPD. Although the natural history of AATD varies, depending in part on what has brought the individual to medical attention (e.g., lung symptoms, liver symptoms, asymptomatic relative of an affected individual), the onset of respiratory disease in smokers with AATD is characteristically between ages 40 and 50 years [<a class="bk_pop" href="#alpha1-a.REF.tanash.2008.1091">Tanash et al 2008</a>]. Nonsmokers may have a normal life span, but can also develop lung and/or liver disease.</p><p>Individuals with severe AATD may manifest the usual signs and symptoms of obstructive lung disease, asthma, and chronic bronchitis (e.g., dyspnea, cough, wheezing, and sputum production) [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.1997.394">McElvaney et al 1997</a>]. For example, in the National Heart, Lung, and Blood Institute Registry, of 1,129 participants with severe deficiency of AAT, 84% described dyspnea, 76% wheezed with an upper respiratory tract infection, and 50% reported cough and phlegm [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.1997.394">McElvaney et al 1997</a>, <a class="bk_pop" href="#alpha1-a.REF.eden.2003.765">Eden et al 2003</a>]. Of note, the prevalence of AATD in persons with asthma does not differ from that found in the general population [<a class="bk_pop" href="#alpha1-a.REF.wencker.2002.319">Wencker et al 2002</a>, <a class="bk_pop" href="#alpha1-a.REF.miravitlles.2003.404">Miravitlles et al 2003</a>].</p><p>Most individuals (~95%) with severe AATD have evidence of bronchiectasis on chest CT, with 27% demonstrating clinical symptoms of bronchiectasis [<a class="bk_pop" href="#alpha1-a.REF.parr.2007.1215">Parr et al 2007</a>].</p><ul><li class="half_rhythm"><div>Chest CT shows loss of lung parenchyma and hyperlucency. In contrast to the usual pattern observed in centriacinar emphysema (emphysematous changes more pronounced in the lung apices than bases), the pattern observed in two thirds of individuals with AATD is that of more pronounced emphysematous changes in the bases than apices [<a class="bk_pop" href="#alpha1-a.REF.parr.2004.1172">Parr et al 2004</a>].</div></li><li class="half_rhythm"><div>Lung function tests show decreased expiratory airflow, increased lung volumes, and decreased diffusing capacity. Approximately 60% of individuals with AATD-associated emphysema demonstrate a component of reversible airflow obstruction, defined as a 200-mL and 12% increase in the post-bronchodilator FEV<sub>1</sub> and/or FVC.</div></li></ul><p><b>Childhood-onset lung disease.</b> Although reported, emphysema in children with AATD is extremely rare and may result from the coexistence of other unidentified genetic factors affecting the lung [<a class="bk_pop" href="#alpha1-a.REF.cox.1979.467">Cox &#x00026; Talamo 1979</a>].</p><p>Studies that followed newborns with severe AAT deficiency through age 32 years showed that most adults did not smoke and lacked physiologic and CT evidence of emphysema [<a class="bk_pop" href="#alpha1-a.REF.mostafavi.2018.3689">Mostafavi et al 2018</a>]. Longer-term follow-up studies are not currently available. In most observational studies, the mean age of individuals with lung disease is in the fifth decade [<a class="bk_pop" href="#alpha1-a.REF.seersholm.1997.2260">Seersholm et al 1997</a>, <a class="bk_pop" href="#alpha1-a.REF.alpha1_antitrypsin_deficiency_registry_study_group.1998.49">Alpha-1 Antitrypsin Deficiency Registry Study Group 1998</a>].</p><p><b>Risk for lung disease in PI*MZ heterozygotes.</b> Approximately 2%-3% of North Americans are PI*MZ heterozygotes. Nonsmoking PI*MZ heterozygotes are generally not considered to be at significantly increased risk for clinical emphysema [<a class="bk_pop" href="#alpha1-a.REF.molloy.2014.419">Molloy et al 2014</a>]. Specifically, population-based studies show no significant spirometric differences between matched PI*MZ and PI*MM cohorts [<a class="bk_pop" href="#alpha1-a.REF.al_ashry.2017.170068">Al Ashry &#x00026; Strange 2017</a>]. However, smoking PI*MZ heterozygotes are at increased risk for COPD [<a class="bk_pop" href="#alpha1-a.REF.hersh.2004.843">Hersh et al 2004</a>, <a class="bk_pop" href="#alpha1-a.REF.s_rheim.2010.1125">S&#x000f8;rheim et al 2010</a>, <a class="bk_pop" href="#alpha1-a.REF.molloy.2014.419">Molloy et al 2014</a>]. Of note, slight abnormalities of lung function can be present without clinical symptoms. Alternatively, spirometry can miss at least 10% of individuals with a clinical diagnosis of COPD and emphysema on CT scan [<a class="bk_pop" href="#alpha1-a.REF.smith.2014.94.e7">Smith et al 2014</a>, <a class="bk_pop" href="#alpha1-a.REF.lutchmedial.2015.176">Lutchmedial et al 2015</a>].</p><p><b>Risk for lung disease in persons with the PI*SZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>.</b> Individuals who smoke and have the PI*SZ genotype with serum AAT levels below the protective threshold value have a slightly increased disease risk.</p><div id="alpha1-a.T.relationship_of_aat_protein_v" class="table"><h3><span class="label">Table 4. </span></h3><div class="caption"><p>Relationship of AAT Protein Variants to Serum AAT Levels and Emphysema Risk in Adults</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.relationship_of_aat_protein_v/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.relationship_of_aat_protein_v_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" style="text-align:left;vertical-align:middle;">AAT Protein Variant</th><th id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2" colspan="3" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Prevalence (%)</th><th id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Serum AAT Levels</th><th id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="2" scope="col" colspan="1" headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" style="text-align:left;vertical-align:middle;">Lifetime<br />Emphysema<br />Risk</th></tr><tr><th headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2" id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">World-wide</th><th headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2" id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">NA</th><th headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2" id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Europe</th><th headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3" id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">"True level"&#x000a0;<sup>1</sup> mean (5th %ile-95th %ile)</th><th headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3" id="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Commercial standard&#x000a0;<sup>2</sup> median (5th %ile-95th %ile)</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>MM</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">96.3</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">93.0</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">91.1</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">33 (20-53)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">147 (102-254)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Background</td></tr><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>MS</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.7</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">4.8</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">6.6</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">33 (18-52)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">125 (86-218)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Background</td></tr><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>MZ</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.8</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">2.1-3</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">1.9</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">25.4 (15-42)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">90 (62-151)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Background</td></tr><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>SS</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.08</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.1</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.3</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">28 (20-48)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">95 (43-154)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">Background</td></tr><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>SZ</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.02</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.1</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.1</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">16.5 (10-23)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">62 (33-108)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">20%-50%</td></tr><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>ZZ</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.003</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0.01</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">5.3 (3.4-7)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">&#x02264;29 (&#x02264;29-52)</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">80%-100%</td></tr><tr><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<b>Null-Null</b>
</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_2 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">-</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_3 hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_2_5" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">0</td><td headers="hd_h_alpha1-a.T.relationship_of_aat_protein_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">100%</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">Adapted from <a class="bk_pop" href="#alpha1-a.REF.brantly.1991.703">Brantly et al [1991]</a>, <a class="bk_pop" href="#alpha1-a.REF.stoller.2005.2225">Stoller &#x00026; Aboussouan [2005]</a>, <a class="bk_pop" href="#alpha1-a.REF.de_serres.2012.277">de Serres &#x00026; Blanco [2012]</a>, <a class="bk_pop" href="#alpha1-a.REF.bornhorst.2013.1000">Bornhorst et al [2013]</a></p></div></dd><dt></dt><dd><div><p class="no_margin">AAT = alpha-1 antitrypsin; NA = North America</p></div></dd><dt>1. </dt><dd><div id="alpha1-a.TF.4.1"><p class="no_margin">&#x000b5;mol/L</p></div></dd><dt>2. </dt><dd><div id="alpha1-a.TF.4.2"><p class="no_margin">mg/dL</p></div></dd></dl></div></div></div><p>Note: An attempt to correlate serum AAT levels with protein variants in children showed trends similar to those seen in adults [<a class="bk_pop" href="#alpha1-a.REF.donato.2012.398">Donato et al 2012</a>].</p></div><div id="alpha1-a.Liver_Disease"><h4>Liver Disease</h4><p><b>Childhood-onset liver disease.</b> The most common manifestation of AATD-associated liver disease is neonatal cholestasis: jaundice, with hyperbilirubinemia and raised serum aminotransferase levels in the early days and months of life.</p><p>Liver abnormalities develop in only a portion of children with AATD. In a study of 200,000 Swedish children who were followed up after newborn screening for AATD, 18% of those with the PI*ZZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> developed clinically recognized liver abnormalities and 2.4% developed liver cirrhosis with death in childhood [<a class="bk_pop" href="#alpha1-a.REF.sveger.1976.1316">Sveger 1976</a>, <a class="bk_pop" href="#alpha1-a.REF.sveger.1988.847">Sveger 1988</a>, <a class="bk_pop" href="#alpha1-a.REF.strnad.2020.1443">Strnad et al 2020</a>]. Liver damage may progress slowly [<a class="bk_pop" href="#alpha1-a.REF.volpert.2000.258">Volpert et al 2000</a>].</p><p>In a follow-up study of 44 children with AATD-associated liver disease initially manifesting as cirrhosis or portal hypertension, outcomes ranged from liver transplantation in two to relatively healthy lives up to 23 years after diagnosis in seven [<a class="bk_pop" href="#alpha1-a.REF.migliazza.2000.5">Migliazza et al 2000</a>].</p><p>It is not known why only a small proportion of children with early hyperbilirubinemia have continued liver destruction leading to cirrhosis. The overall risk that an individual with the PI*ZZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> will develop severe liver disease in childhood is generally low (~2%); the risk is higher among sibs of a child with the PI*ZZ genotype and liver disease.</p><ul><li class="half_rhythm"><div>When liver abnormalities in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> are mild and resolve, the risk of liver disease in sibs with the PI*ZZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> is approximately 13%.</div></li><li class="half_rhythm"><div>When liver disease in the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> is severe, the risk for severe liver disease in sibs with the PI*ZZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> may be approximately 40% [<a class="bk_pop" href="#alpha1-a.REF.cox.2004.468">Cox 2004</a>].</div></li></ul><p>The PI*MZ and PI*SZ genotypes are not associated with an increased risk for childhood liver disease; however, on occasion, elevated levels of liver enzymes that resolve have been observed. In a study of 58 children with <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> genotypes showing signs of liver involvement during the first six months of life, almost all had normal values of liver enzymes at ages 12 months, five years, and ten years [<a class="bk_pop" href="#alpha1-a.REF.pittschieler.2002.239">Pittschieler 2002</a>].</p><p><b>Adult-onset liver disease.</b> Liver disease in adults (manifesting as cirrhosis and fibrosis) may occur in the absence of a history of neonatal or childhood liver disease. Liver disease is more common in men than women.</p><p>The risk for liver disease at age 20-40 years is approximately 2% and at age 41-50 years approximately 4% [<a class="bk_pop" href="#alpha1-a.REF.cox.1983.221">Cox &#x00026; Smyth 1983</a>].</p><p>Autopsy studies suggest that the prevalence of liver disease may be as high as 40% in older individuals who have never smoked and do not have COPD [<a class="bk_pop" href="#alpha1-a.REF.eriksson.1987.461">Eriksson 1987</a>]. Liver disease was subclinical at death in some of these individuals.</p><p><b>Hepatocellular carcinoma (HCC).</b> The risk for HCC among individuals with AATD and the PI*ZZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> is several times that typically associated with liver cirrhosis. This increased risk has been attributed to failure of apoptosis of injured cells with retained Z protein, which sends a chronic regeneration signal to hepatocytes with a lesser load of retained Z protein [<a class="bk_pop" href="#alpha1-a.REF.perlmutter.2006.233">Perlmutter 2006</a>].</p><p><b>Liver pathology.</b> AATD liver inclusions are visualized as bright pink globules of various sizes, using periodic acid-Schiff (PAS) stain following diastase treatment (PAS-D). The extent of inclusion formation varies considerably; the number and size of liver inclusions increases with age. Inclusions are not observed before age 12 weeks. Note: Liver biopsy, when indicated in the evaluation of individuals with liver disease, may show PAS positive diastase-resistant inclusion bodies which are suggestive of but not pathognomonic for AATD.</p><p>In infants with AATD, inclusions may be fine and granular and difficult to identify in percutaneous liver biopsy specimens. They are also observed in bile duct epithelium [<a class="bk_pop" href="#alpha1-a.REF.cutz.1979.1">Cutz &#x00026; Cox 1979</a>].</p><p>Liver inclusions indicate the presence of at least one PI*Z <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>; histologic examination of the liver cannot confidently distinguish between PI*MZ heterozygotes and PI*ZZ homozygotes, although inclusions are generally more profuse in PI*ZZ homozygotes. Visualization of inclusions may be variable among PI*MZ heterozygotes.</p></div><div id="alpha1-a.Other_Disease_Associations"><h4>Other Disease Associations</h4><p>Panniculitis occurs in an estimated one in 1,000 individuals with AATD [<a class="bk_pop" href="#alpha1-a.REF.alpha1_antitrypsin_deficiency_registry_study_group.1998.49">Alpha-1 Antitrypsin Deficiency Registry Study Group 1998</a>]. Panniculitis characteristically presents as migratory, inflammatory, tender skin nodules which may ulcerate [<a class="bk_pop" href="#alpha1-a.REF.stoller.2008.113">Stoller &#x00026; Piliang 2008</a>]. Sites of trauma (e.g., legs, lower abdomen) are most commonly affected. Presumably like emphysema in the lung, panniculitis in the skin is caused by unopposed proteolytic damage produced by the PI*Z <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a>.</p><p>Individuals with AATD appear to have increased susceptibility to C-ANCA-positive vasculitis (e.g., granulomatosis with polyangiitis [GPA], previously called Wegener granulomatosis) [<a class="bk_pop" href="#alpha1-a.REF.hadzikblaszczyk.2018.9">Hadzik-Blaszczyk et al 2018</a>].</p></div></div><div id="alpha1-a.GenotypePhenotype_Correlations"><h3>Genotype-Phenotype Correlations</h3><p>The risk for lung disease associated with the following <i>SERPINA1</i> genotypes is summarized in <a href="/books/NBK1519/table/alpha1-a.T.relationship_of_aat_protein_v/?report=objectonly" target="object" rid-ob="figobalpha1aTrelationshipofaatproteinv">Table 4</a>.</p><p><b>PI*MM.</b> This <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> is associated with a normal serum concentration of AAT and no increased risk of liver or lung disease.</p><p><b>PI*MZ.</b> In general, nonsmoking individuals with this <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> are not considered to be at increased risk for lung disease; PI*MZ smokers and those with environmental exposures have increased risk of developing COPD [<a class="bk_pop" href="#alpha1-a.REF.molloy.2014.419">Molloy et al 2014</a>, <a class="bk_pop" href="#alpha1-a.REF.al_ashry.2017.170068">Al Ashry &#x00026; Strange 2017</a>].</p><p><b>PI*SS.</b> This <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> does not appear to be associated with an increased risk for clinical disease [<a class="bk_pop" href="#alpha1-a.REF.ferrarotti.2012.669">Ferrarotti et al 2012</a>]. The S <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is most common among individuals of Iberian descent.</p><p><b>PI*SZ.</b> This <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> is not usually associated with a high risk for liver or lung disease; however, about 11% of individuals with the PI*SZ genotype have serum AAT levels below the protective threshold value (11 &#x003bc;M). Those individuals are at increased risk of developing emphysema with lower zone predominance, as well as chronic bronchitis, especially if they are smokers [<a class="bk_pop" href="#alpha1-a.REF.green.2015.939">Green et al 2015</a>].</p><p><b>PI*ZZ.</b> Individuals with this <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> have a serum concentration of AAT that is approximately 10%-20% of normal (serum levels of 20-35 mg/dL) and are at high risk for both liver and lung disease. This genotype is present in 95% of affected individuals with clinical manifestations of AATD. Variable disease expressivity in individuals with the PI*ZZ genotype &#x02013; not accounted for by the presence of known risk factors such as cigarette smoking &#x02013; suggests the existence of other as-yet unidentified genetic disease modifiers.</p><p><b>PI*FF.</b> While rare, the F <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> is associated with AAT that is functionally impaired in binding neutrophil elastase but is quantitatively normal. Individuals with the PI*FF or PI*FZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> are deemed to be at increased risk of developing emphysema [<a class="bk_pop" href="#alpha1-a.REF.sinden.2014.132">Sinden et al 2014</a>].</p><p><b>PI*<a class="def" href="/books/n/gene/glossary/def-item/null/">null</a>-null</b> (sometimes designated PI*QO). Individuals with this <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> have no measurable serum AAT secondary to complete lack of synthesis of AAT. Because protein does not accumulate in the liver, these individuals are not at increased risk of developing liver disease; however, they are at high risk of developing lung disease.</p></div><div id="alpha1-a.Nomenclature"><h3>Nomenclature</h3><p>In some publications, the term alpha-1-protease inhibitor is substituted for alpha-1 antitrypsin (AAT).</p><p>PI*M is used to describe normal alleles. Different normal alleles are given numeric designations (e.g., PI*M1, PI*M2).</p></div><div id="alpha1-a.Prevalence"><h3>Prevalence</h3><p>AATD is one of the most common metabolic disorders in persons of northern European heritage, occurring in approximately one in 5,000-7,000 individuals in North America and one in 1,500-3,000 in Scandinavia. AATD also occurs (in lower frequencies) in all other racial subgroups worldwide [<a class="bk_pop" href="#alpha1-a.REF.campbell.2000">Campbell 2000</a>, <a class="bk_pop" href="#alpha1-a.REF.miravitlles.2000">Miravitlles 2000</a>, <a class="bk_pop" href="#alpha1-a.REF.de_serres.2012.277">de Serres &#x00026; Blanco 2012</a>].</p></div></div><div id="alpha1-a.Genetically_Related_Allelic_Dis"><h2 id="_alpha1-a_Genetically_Related_Allelic_Dis_">Genetically Related (Allelic) Disorders</h2><p>No phenotypes other than those discussed in this <i>GeneReview</i> are known to be associated with pathogenic variants in <i>SERPINA1</i>.</p></div><div id="alpha1-a.Differential_Diagnosis"><h2 id="_alpha1-a_Differential_Diagnosis_">Differential Diagnosis</h2><div id="alpha1-a.Lung_Disease_1"><h3>Lung Disease</h3><p>Differential diagnoses include disorders causing chronic obstructive pulmonary disease (COPD), such as emphysema, chronic bronchitis, and bronchiectasis.</p><p><a class="bk_pop" href="#alpha1-a.REF.boss_.2019.427">Boss&#x000e9; et al [2019]</a> have described an <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a> predisposition to emphysema in a single large French Canadian family that affects the protein, tyrosine phosphatase non-receptor, type 6 (PTPN6). As with severe deficiency of AAT, in this newly described condition there is near-complete <a class="def" href="/books/n/gene/glossary/def-item/penetrance/">penetrance</a> for emphysema that is lower-lobe predominant and can be early onset (i.e., 4th-5th decade). Unlike alpha-1 antitrypsin deficiency (AATD), <i>PTPN6</i>-type emphysema is inherited as an autosomal dominant condition.</p></div><div id="alpha1-a.Liver_Disease_1"><h3>Liver Disease</h3><p>See <a href="/books/NBK1519/table/alpha1-a.T.genetic_disorders_associated/?report=objectonly" target="object" rid-ob="figobalpha1aTgeneticdisordersassociated">Table 5</a> for genetic disorders to consider in the differential diagnosis of AATD-related liver disease. The differential diagnosis of neonatal cholestasis also includes multiple metabolic diseases and other non-hereditary diseases including extrahepatic biliary atresia and gestational alloimmune liver disease (formerly known as neonatal hemochromatosis). Acquired disorders to consider include chronic viral hepatitis, alcoholic and non-alcoholic steatohepatitis, sclerosing cholangitis, and primary biliary cholangitis.</p><div id="alpha1-a.T.genetic_disorders_associated" class="table"><h3><span class="label">Table 5. </span></h3><div class="caption"><p>Genetic Disorders Associated with Liver Disease in the Differential Diagnosis of Alpha-1 Antitrypsin Deficiency</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.genetic_disorders_associated/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.genetic_disorders_associated_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" rowspan="2" scope="col" colspan="1" headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" style="text-align:left;vertical-align:middle;">Gene(s)</th><th id="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="2" scope="col" colspan="1" headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" style="text-align:left;vertical-align:middle;">Disorder</th><th id="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="2" scope="col" colspan="1" headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" style="text-align:left;vertical-align:middle;">MOI</th><th id="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4" colspan="2" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Clinical Features of Differential Diagnosis Disorder</th></tr><tr><th headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4" id="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" colspan="1" scope="colgroup" rowspan="1" style="text-align:left;vertical-align:middle;">Overlapping w/AATD</th><th headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4" id="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Distinguishing from AATD</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>ABCB11</i>
<br />
<i>ABCB4</i>
<br />
<i>ATPB1</i>
<br />
<i>NR1H4</i>
<br />
<i>TJP2</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Progressive <a class="def" href="/books/n/gene/glossary/def-item/familial/">familial</a> intrahepatic cholestasis (PFIC) (See OMIM <a href="https://omim.org/phenotypicSeries/PS211600" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">PS211600</a> &#x00026; <a href="/books/n/gene/pfic/">ATPB1 Deficiency</a>.)</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cholestasis can be prominent; presentation in infancy is common.</div></li><li class="half_rhythm"><div>Risk for hepatocellular carcinoma in PFIC2 &#x00026; AATD is higher than in other liver diseases.</div></li></ul>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Often &#x02193; or normal GGT, differing histologic appearance on liver biopsy</div></li><li class="half_rhythm"><div>Other extrahepatic manifestations may incl hearing loss, diarrhea, pancreatitis, failure to thrive, fat-soluble vitamin deficiencies.</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>ABCC2</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dubin-Johnson syndrome (OMIM <a href="https://omim.org/entry/237500" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">237500</a>)</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Jaundice in infancy w/both direct &#x00026; indirect hyperbilirubinemia</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Normal liver histology is normal (though liver is black in color); ALT &#x00026; AST also normal</div></li><li class="half_rhythm"><div>&#x02191; fractional excretion of coproporphyrin I</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>ATP7B</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/wilson/">Wilson disease</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Chronic liver disease</div></li><li class="half_rhythm"><div>May present beyond newborn period; presentation in teen yrs common</div></li></ul>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>May be accompanied by neurologic &#x00026;/or psychiatric symptoms; Kayser-Fleischer rings in 50% of those w/hepatic disease; &#x02193; serum ceruloplasmin &#x00026; &#x02191; urinary copper excretion</div></li><li class="half_rhythm"><div>Acute liver failure is assoc w/hemolysis &#x00026; &#x02193; serum alkaline phosphatase.</div></li><li class="half_rhythm"><div>Liver biopsy shows excess copper accumulation &#x00026; steatosis.</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>CFTR</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/cf/">Cystic fibrosis</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Cholestasis in infancy</div></li><li class="half_rhythm"><div>Liver disease can become more apparent in older children.</div></li></ul>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Extrahepatic obstruction due to inspissated bile or bile plugs</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>HAMP</i>
<br />
<i>HJV</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/jh/">Juvenile hereditary hemochromatosis</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Presentation can be in early childhood &#x00026; adolescence.</div></li><li class="half_rhythm"><div>Liver disease may not be prominent.</div></li></ul>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>&#x02191; serum ferritin &#x00026; transferrin saturations</div></li><li class="half_rhythm"><div>Greater likelihood of cardiac involvement (cardiomyopathy), &#x02193; glucose tolerance, &#x00026; hypogonadism</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>HFE</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/hemochromatosis/"><i>HFE</i> hemochromatosis</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Liver disease can be relatively asymptomatic.</div></li><li class="half_rhythm"><div>&#x02191; risk for hepatocellular carcinoma</div></li></ul>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>&#x02191; ferritin</div></li><li class="half_rhythm"><div>Iron overload in liver &#x00026; other organs, primarily after age 40 yrs</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>JAG1</i>
<br />
<i>NOTCH2</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/alagille/">Alagille syndrome</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Presents in early infancy</div></li><li class="half_rhythm"><div>Cholestasis</div></li></ul>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Syndrome assoc w/several <a class="def" href="/books/n/gene/glossary/def-item/congenital/">congenital</a> defects (cardiac, vertebral, renal, ophthalmic, &#x00026; <a class="def" href="/books/n/gene/glossary/def-item/dysmorphic/">dysmorphic</a> features)</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>SLC40A1</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Type 4 hemochromatosis<br />(OMIM <a href="https://omim.org/entry/606069" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">606069</a>)</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AD</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May present w/chronic fatigue</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Ferroportin disease caused by <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> variants is characterized by &#x02191; ferritin levels, &#x02191; macrophage iron, &#x02193; transferrin saturation, mild anemia, &#x00026; minimal hepatic iron deposition.</div></li><li class="half_rhythm"><div>Ferroportin disease caused by <a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a> variants is similar to classic HFE.</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>SLCO1B1</i>
<br />
<i>SLCO1B3</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/rotor/">Rotor syndrome</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR <a class="def" href="/books/n/gene/glossary/def-item/digenic/">digenic</a></td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Jaundice in infancy w/both direct &#x00026; indirect hyperbilirubinemia</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Normal liver histology; normal color liver tissue, normal ALT &#x00026; AST</div></li><li class="half_rhythm"><div>&#x02191; total urinary coproporphyrin excretion w/&#x02191; fractional excretion of coprophyrin I</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<i>TFR2</i>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="/books/n/gene/tfr2/"><i>TFR2</i> hereditary hemochromatosis</a>
</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">AR</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_1" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Intermediate severity</td><td headers="hd_h_alpha1-a.T.genetic_disorders_associated_1_1_1_4 hd_h_alpha1-a.T.genetic_disorders_associated_1_1_2_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">&#x02193; hepcidin levels &#x00026; iron overload</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AATD = alpha-1 antitrypsin deficiency; AD = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-dominant/">autosomal dominant</a>; ALT = alanine aminotransferase; AR = <a class="def" href="/books/n/gene/glossary/def-item/autosomal-recessive/">autosomal recessive</a>; AST = aspartate transaminase; GGT = gamma-glutamyl transferase; HFE = hemochromatosis; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd></dl></div></div></div></div></div><div id="alpha1-a.Management"><h2 id="_alpha1-a_Management_">Management</h2><div id="alpha1-a.Evaluations_Following_Initial_D"><h3>Evaluations Following Initial Diagnosis</h3><p>To establish the extent of disease and needs in an individual diagnosed with alpha-1 antitrypsin deficiency (AATD), the evaluations summarized in <a href="/books/NBK1519/table/alpha1-a.T.recommended_evaluations_follo/?report=objectonly" target="object" rid-ob="figobalpha1aTrecommendedevaluationsfollo">Table 6</a> (if not performed as part of the evaluation that led to the diagnosis) are recommended.</p><div id="alpha1-a.T.recommended_evaluations_follo" class="table"><h3><span class="label">Table 6. </span></h3><div class="caption"><p>Recommended Evaluations Following Initial Diagnosis in Individuals with AATD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.recommended_evaluations_follo/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.recommended_evaluations_follo_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Lungs</b>
</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function tests</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Include:
<ul><li class="half_rhythm"><div>Spirometry (w/post-bronchodilator testing)</div></li><li class="half_rhythm"><div>Lung volumes</div></li><li class="half_rhythm"><div>Diffusing capacity</div></li><li class="half_rhythm"><div>Measures of oxygenation</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">Chest CT</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">More sensitive for detecting emphysema than pulmonary function tests</td></tr><tr><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Liver</b>
</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Liver biopsy</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">For light microscopy &#x00026; histochemistry when definition of precise nature &#x00026; extent of liver disease is clinically indicated</td></tr><tr><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Skin</b>
</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Detailed history &#x00026; physical exam</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Assess for panniculitis</td></tr><tr><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Genetic</b>
<br />
<b>counseling</b>
</td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">By genetics professionals&#x000a0;<sup>1</sup></td><td headers="hd_h_alpha1-a.T.recommended_evaluations_follo_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">To inform affected persons &#x00026; families re nature, MOI, &#x00026; implications of AATD to facilitate medical &#x00026; personal decision making</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AATD = alpha-1 antitrypsin deficiency; MOI = <a class="def" href="/books/n/gene/glossary/def-item/mode-of-inheritance/">mode of inheritance</a></p></div></dd><dt>1. </dt><dd><div id="alpha1-a.TF.6.1"><p class="no_margin">Medical geneticist, certified genetic counselor, certified advanced genetic nurse</p></div></dd></dl></div></div></div></div><div id="alpha1-a.Treatment_of_Manifestations"><h3>Treatment of Manifestations</h3><div id="alpha1-a.T.treatment_of_manifestations_i" class="table"><h3><span class="label">Table 7. </span></h3><div class="caption"><p>Treatment of Manifestations in Individuals with AATD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.treatment_of_manifestations_i/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.treatment_of_manifestations_i_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Manifestation/Concern</th><th id="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Treatment</th><th id="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Considerations/Other</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Lung disease</b>
</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Varies by type of lung disease</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>COPD</b>
</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Standard therapy incl ICS, LABA, long-acting muscarinic antagonists, pulmonary rehabilitation, supplemental oxygen, &#x00026; vaccinations (e.g., influenza &#x00026; pneumococcal)</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Although the inflammation of COPD is generally poorly responsive to ICS, a randomized study indicates that ICS may reduce dynamic hyperinflation, improve FEV<sub>1</sub>, walking distance, &#x00026; dyspnea when added to LABA in AATD [<a class="bk_pop" href="#alpha1-a.REF.corda.2008.61">Corda et al 2008</a>].</td></tr><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Emphysema</b>
</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Augmentation therapy w/periodic intravenous infusion of pooled human serum AAT</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"><ul><li class="half_rhythm"><div>Used in those w/established emphysema</div></li><li class="half_rhythm"><div>The greatest benefit of this therapy is observed in individuals w/moderate degrees of airflow obstruction (e.g., FEV<sub>1</sub> 35%-60% predicted)</div></li><li class="half_rhythm"><div>Hospitalizations &#x00026; COPD exacerbations may &#x02191; after interruption of augmentation [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.2020.1478">McElvaney et al 2020</a>].</div></li></ul>
</td></tr><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>End-stage lung disease (FEV<sub>1</sub> &#x0003c;30%)</b>
</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Lung transplantation</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">May have &#x02191; short-term complications perhaps related to discontinuation of augmentation before transplantation, w/improved long-term survival relative to AATD replete COPD [<a class="bk_pop" href="#alpha1-a.REF.kleinerova.2019.1900055">Kleinerova et al 2019</a>, <a class="bk_pop" href="#alpha1-a.REF.spratt.2019.1130">Spratt et al 2019</a>]</td></tr><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" rowspan="2" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Liver disease</b>
</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Liver transplantation for severe disease</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Will restore AAT levels</td></tr><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" colspan="1" scope="col" rowspan="1" style="text-align:left;vertical-align:middle;">Vaccinations against hepatitis A &#x00026; B</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr><tr><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Panniculitis</b>
</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Dapsone or doxycycline therapy; if refractory to this, high-dose intravenous AAT augmentation therapy [<a class="bk_pop" href="#alpha1-a.REF.stoller.2008.113">Stoller &#x00026; Piliang 2008</a>]</td><td headers="hd_h_alpha1-a.T.treatment_of_manifestations_i_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;"></td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency; COPD = chronic obstructive pulmonary disease; ICS = inhaled corticosteroids; LABA = long-acting beta agonists</p></div></dd></dl></div></div></div></div><div id="alpha1-a.Surveillance"><h3>Surveillance</h3><div id="alpha1-a.T.recommended_surveillance_for" class="table"><h3><span class="label">Table 8. </span></h3><div class="caption"><p>Recommended Surveillance for Individuals with AATD</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.recommended_surveillance_for/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.recommended_surveillance_for_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">System/Concern</th><th id="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Evaluation</th><th id="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Frequency</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Lung disease</b>
</td><td headers="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Pulmonary function tests (incl spirometry w/bronchodilators &#x00026; diffusing capacity measurements)</td><td headers="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_3" rowspan="2" colspan="1" style="text-align:left;vertical-align:middle;">Every 6-12 mos [<a class="bk_pop" href="#alpha1-a.REF.attaway.2019.2089">Attaway et al 2019</a>]</td></tr><tr><td headers="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_1" scope="row" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">
<b>Liver disease</b>
</td><td headers="hd_h_alpha1-a.T.recommended_surveillance_for_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Liver function tests, platelet count &#x00026; liver ultrasound, elastography (e.g., FibroScan), MRI</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">MRI = magnetic resonance imaging</p></div></dd></dl></div></div></div></div><div id="alpha1-a.AgentsCircumstances_to_Avoid"><h3>Agents/Circumstances to Avoid</h3><p>Avoid the following:</p><ul><li class="half_rhythm"><div>Smoking (both active and passive)</div></li><li class="half_rhythm"><div>Occupational exposure (including exposure to environmental pollutants used in agriculture, mineral dust, gas, and fumes)</div></li><li class="half_rhythm"><div>Excessive use of alcohol</div></li></ul></div><div id="alpha1-a.Evaluation_of_Relatives_at_Risk"><h3>Evaluation of Relatives at Risk</h3><p>The Alpha-1 Foundation-sponsored update of the ATS/ERS guidelines [<a class="bk_pop" href="#alpha1-a.REF.sandhaus.2016.668">Sandhaus et al 2016</a>] and the European Respiratory Society statement [<a class="bk_pop" href="#alpha1-a.REF.miravitlles.2017.1700610">Miravitlles et al 2017</a>] recommend evaluation of sibs, parents, and the children of an individual with severe AATD (see <a href="/books/NBK1519/table/alpha1-a.T.clinical_indications_for_gene/?report=objectonly" target="object" rid-ob="figobalpha1aTclinicalindicationsforgene">Table 2</a>) in order to identify as early as possible those who would benefit from <a href="#alpha1-a.Surveillance">surveillance</a>, institution of treatment, and preventive measures.</p><p>Extended <a class="def" href="/books/n/gene/glossary/def-item/pedigree/">pedigree</a> analysis beyond first-degree relatives may be indicated in selected instances. For example, the presence of an AATD-associated condition (e.g., chronic obstructive pulmonary disease [COPD], liver disease, panniculitis) in a more distant family member and/or the finding that a parent of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> has the PI*ZZ <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a> would justify extensive family testing (i.e., of family members beyond parents, sibs, and offspring) [<a class="bk_pop" href="#alpha1-a.REF.miravitlles.2017.1700610">Miravitlles et al 2017</a>].</p><p>See <a href="#alpha1-a.Related_Genetic_Counseling_Issu">Genetic Counseling</a> for issues related to testing of at-risk relatives for <a class="def" href="/books/n/gene/glossary/def-item/genetic-counseling/">genetic counseling</a> purposes.</p></div><div id="alpha1-a.Pregnancy_Management"><h3>Pregnancy Management</h3><p>Management of women with AATD during pregnancy should be guided by usual care principles, both for women without clinical disease and for those with liver disease. As noted, emphysema, especially in nonsmokers, would not commonly be expected during the usual childbearing age range.</p></div><div id="alpha1-a.Therapies_Under_Investigation"><h3>Therapies Under Investigation</h3><p>Many novel therapies for AATD are currently under investigation. Studies to slow the progression of lung disease include a variety of strategies: inhaled alpha-1 antitrypsin (AAT), liquid AAT, recombinant AAT, alternate dosing regimens of intravenous augmentation therapy (including double-dose strategies), an oral neutrophil elastase inhibitor, an orally available corrector molecule designed to restore secretion and acute phase reactivity, molecules to block polymer formation, and <a class="def" href="/books/n/gene/glossary/def-item/gene-therapy/">gene therapy</a> using various viral vectors and delivery routes. Placement of valves endoscopically to improve lung function and functional status is also being studied. Examples of studies directed at the AATD-related liver disease include use of carbamazepine or sirolimus to increase autophagy and use of small interfering RNA to suppress aberrant AAT protein translation.</p><p>Search <a href="https://clinicaltrials.gov/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">ClinicalTrials.gov</a> in the US and <a href="https://www.clinicaltrialsregister.eu/ctr-search/search" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">EU Clinical Trials Register</a> in Europe for access to information on these clinical studies.</p></div></div><div id="alpha1-a.Genetic_Counseling"><h2 id="_alpha1-a_Genetic_Counseling_">Genetic Counseling</h2><p>
<i>Genetic counseling is the process of providing individuals and families with
information on the nature, mode(s) of inheritance, and implications of genetic disorders to help them
make informed medical and personal decisions. The following section deals with genetic
risk assessment and the use of family history and genetic testing to clarify genetic
status for family members; it is not meant to address all personal, cultural, or
ethical issues that may arise or to substitute for consultation with a genetics
professional</i>. &#x02014;ED.</p><div id="alpha1-a.Mode_of_Inheritance"><h3>Mode of Inheritance</h3><p>Alpha-1 antitrypsin deficiency (AATD) is inherited in an <a class="def" href="/books/n/gene/glossary/def-item/autosomal/">autosomal</a> <a class="def" href="/books/n/gene/glossary/def-item/codominant/">codominant</a> manner.</p></div><div id="alpha1-a.Risk_to_Family_Members"><h3>Risk to Family Members</h3><p>
<b>Parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
</p><ul><li class="half_rhythm"><div>Either both parents of an individual with AATD are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for one <i>SERPINA1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (e.g., PI*MZ or PI*SZ) or, less frequently, a parent may be <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> for the PI*Z <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> (i.e., PI*ZZ).</div></li><li class="half_rhythm"><div>Molecular genetic testing is recommended for the parents of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> to confirm their genetic status and to allow reliable <a class="def" href="/books/n/gene/glossary/def-item/recurrence-risk/">recurrence risk</a> assessment (see also Management, <a href="#alpha1-a.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a>).</div></li><li class="half_rhythm"><div>In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PI*MZ heterozygotes who have smoked are at increased risk for emphysema (see <a href="#alpha1-a.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a> for additional information regarding risk of lung disease in heterozygotes).</div></li></ul><p>
<b>Sibs of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
</p><ul><li class="half_rhythm"><div>If both parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> (e.g., PI*MZ) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of an affected individual has a 25% chance of being affected (i.e., PI*ZZ), a 50% chance of being heterozygous (i.e., PI*MZ), and a 25% chance of inheriting neither of the pathogenic variants (i.e., PI*MM).</div></li><li class="half_rhythm"><div>If one parent is <a class="def" href="/books/n/gene/glossary/def-item/homozygous/">homozygous</a> (i.e., PI*ZZ) for <a class="def" href="/books/n/gene/glossary/def-item/biallelic/">biallelic</a> pathogenic variants and the other parent is <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> (e.g., PI*MZ) for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib has a 50% chance of being affected (i.e., PI*ZZ) and a 50% chance of being heterozygous (e.g., PI*MZ).</div></li><li class="half_rhythm"><div>In general, nonsmoking heterozygotes are not considered to be at increased risk for lung disease; however, PI*MZ heterozygotes who have smoked are at increased risk for emphysema (see <a href="#alpha1-a.GenotypePhenotype_Correlations">Genotype-Phenotype Correlations</a> for additional information regarding risk of lung disease in heterozygotes).</div></li><li class="half_rhythm"><div>Molecular genetic testing should be offered to all sibs in order to clarify their genetic status and identify as early as possible those who would benefit from <a href="#alpha1-a.Surveillance">surveillance</a>, institution of treatment, and preventive measures.</div></li></ul><p>
<b>Offspring of a <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a></b>
</p><ul><li class="half_rhythm"><div>Unless an individual with AATD has children with an affected individual or a <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a>, offspring will be <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> for a <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> (e.g., PI*MZ).</div></li><li class="half_rhythm"><div>In populations with a high <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> frequency and/or a high rate of <a class="def" href="/books/n/gene/glossary/def-item/consanguinity/">consanguinity</a>, the reproductive partner of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a> may also have one or more <i>SERPINA1</i> pathogenic variants. Thus, the risk to offspring is most accurately determined after (a) protease inhibitor (PI) typing by <a class="def" href="/books/n/gene/glossary/def-item/isoelectric-focusing/">isoelectric focusing</a> of serum or (b) <i>SERPINA1</i> <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> of the proband's reproductive partner.</div></li></ul><p><b>Other family members.</b> If the parents are <a class="def" href="/books/n/gene/glossary/def-item/heterozygous/">heterozygous</a> (e.g., PI*MZ) for a <i>SERPINA1</i> <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a>, each sib of the <a class="def" href="/books/n/gene/glossary/def-item/proband/">proband</a>'s parents is at a 50% risk of being heterozygous for a pathogenic variant (e.g., PI*MZ).</p></div><div id="alpha1-a.Heterozygote_Detection"><h3>Heterozygote Detection</h3><p>Targeted <a class="def" href="/books/n/gene/glossary/def-item/molecular-genetic-testing/">molecular genetic testing</a> for at-risk relatives requires prior identification of the <i>SERPINA1</i> pathogenic variants in the family. If the pathogenic variants in the family have not been identified, <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> testing by protease inhibitor (PI) typing by <a class="def" href="/books/n/gene/glossary/def-item/isoelectric-focusing/">isoelectric focusing</a> of serum or <i>SERPINA1</i> <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> and <a class="def" href="/books/n/gene/glossary/def-item/deletion-duplication-analysis/">deletion/duplication analysis</a> are options.</p><p>Note: Measurement of serum AAT level is not reliable for determining <a class="def" href="/books/n/gene/glossary/def-item/carrier/">carrier</a> status because the range of serum AAT levels among most carriers may overlap the normal serum range [<a class="bk_pop" href="#alpha1-a.REF.bornhorst.2013.1000">Bornhorst et al 2013</a>]. In addition, AAT is an acute-phase reactant and therefore serum AAT levels in a <a class="def" href="/books/n/gene/glossary/def-item/heterozygote/">heterozygote</a> may be elevated during periods of acute inflammation, thereby confounding the diagnosis of deficiency.</p></div><div id="alpha1-a.Related_Genetic_Counseling_Issu"><h3>Related Genetic Counseling Issues</h3><p>See Management, <a href="#alpha1-a.Evaluation_of_Relatives_at_Risk">Evaluation of Relatives at Risk</a> for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.</p><p><b>Risk to sibs of developing severe liver disease in infancy</b>. Although the age of onset, severity, type of symptoms, and rate of progression of AATD cannot be predicted in sibs based on <a class="def" href="/books/n/gene/glossary/def-item/genotype/">genotype</a>, some estimates are available on the risk to sibs of developing severe liver disease in infancy [<a class="bk_pop" href="#alpha1-a.REF.cox.2004.468">Cox 2004</a>].</p><ul><li class="half_rhythm"><div>If the parents are heterozygotes (e.g., PI*MZ) but have not had a child with severe liver disease, the risk to offspring of having AATD (25%) AND severe liver disease in childhood (13.6%) is less than 1% (0.64%).</div></li><li class="half_rhythm"><div>If an affected individual died from severe liver disease in childhood, the risk to sibs of having AATD (25%) AND severe liver disease in childhood (40%) is 10%.</div></li><li class="half_rhythm"><div>If an affected individual did not have severe liver disease in childhood or if the liver disease resolved, the risk to sibs of having AATD (25%) AND liver disease (13%) is 3.3%.</div></li></ul><p><b>Family planning.</b> The optimal time for determination of genetic risk, clarification of genetic status, and discussion of the availability of prenatal/<a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> is before pregnancy.</p><p><b>DNA banking.</b> Because it is likely that testing methodology and our understanding of genes, pathogenic mechanisms, and diseases will improve in the future, consideration should be given to banking DNA from probands in whom a molecular diagnosis has not been confirmed (i.e., the causative pathogenic mechanism is unknown). For more information, see <a class="bk_pop" href="#alpha1-a.REF.huang.2022.389">Huang et al [2022]</a>.</p></div><div id="alpha1-a.Prenatal_Testing_and_Preimplant"><h3>Prenatal Testing and Preimplantation Genetic Testing</h3><p>Once the <i>SERPINA1</i> pathogenic variants have been identified in an affected family member, prenatal and <a class="def" href="/books/n/gene/glossary/def-item/preimplantation-genetic-testing/">preimplantation genetic testing</a> for AATD are possible.</p><p>Note: Prenatal testing is not useful in predicting age of onset, severity, type of symptoms, or rate of progression of the disorder. Fetal testing is not recommended in the American Thoracic Society/European Respiratory Society <a href="#alpha1-a.Published_Guidelines__Consensus">guidelines</a> or in most other available guidelines [<a class="bk_pop" href="#alpha1-a.REF.attaway.2019.2089">Attaway et al 2019</a>] because of the <a class="def" href="/books/n/gene/glossary/def-item/variable-expressivity/">variable expressivity</a> of disease and the possibility that individuals with severe deficiency of AAT can have a normal life span and escape disease, especially if they never smoke [<a class="bk_pop" href="#alpha1-a.REF.american_thoracic_society_european_respiratory_society.2003.818">American Thoracic Society &#x00026; European Respiratory Society 2003</a>]. Because some children with AATD develop severe liver disease in the newborn period and some of these children have a poor outcome, <a class="def" href="/books/n/gene/glossary/def-item/prenatal-diagnosis/">prenatal diagnosis</a> may be of interest to some at-risk couples who have previously had a child with severe liver disease (see <a href="#alpha1-a.Related_Genetic_Counseling_Issu">Related Genetic Counseling Issues</a>, <b>Risk to sibs of developing severe liver disease in infancy</b>).</p><p>Differences in perspective may exist among medical professionals and within families regarding the use of <a class="def" href="/books/n/gene/glossary/def-item/prenatal-testing/">prenatal testing</a>. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.</p></div></div><div id="alpha1-a.Resources"><h2 id="_alpha1-a_Resources_">Resources</h2><p>
<i>GeneReviews staff has selected the following disease-specific and/or umbrella
support organizations and/or registries for the benefit of individuals with this disorder
and their families. GeneReviews is not responsible for the information provided by other
organizations. For information on selection criteria, click <a href="/books/n/gene/app4/">here</a>.</i></p>
<ul><li class="half_rhythm"><div>
<b>Alpha-1 Advocacy Alliance</b>
</div><div>103 Rapidan Church Lane</div><div>PO Box 202</div><div>Wolftown VA 22748</div><div><b>Phone:</b> 866-367-2122 (toll-free); 540-948-6777</div><div><b>Fax:</b> 540-948-6763</div><div><b>Email:</b> alpha1advocacyalliance@yahoo.com</div><div>
<a href="https://www.alpha1.org/Newly-Diagnosed/Living-with-Alpha-1/Support-Groups" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Alpha-1 Advocacy Alliance</a>
</div></li><li class="half_rhythm"><div>
<b>Alpha-1 Canada</b>
</div><div>13300 Tecumseh Road East,</div><div>Suite 241</div><div>Tecumseh Ontario N8N 4R8</div><div>Canada</div><div><b>Phone:</b> 888-669-4583 (toll-free); 519-258-1444</div><div><b>Fax:</b> 519-258-1614</div><div><b>Email:</b> info@alpha1canada.ca</div><div>
<a href="http://www.alpha1canada.ca" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">www.alpha1canada.ca</a>
</div></li><li class="half_rhythm"><div>
<b>Alpha-1 Foundation</b>
</div><div>3300 Ponce de Leon Boulevard</div><div>Coral Gables FL 33134</div><div><b>Phone:</b> 877-228-7321; 305-567-9888</div><div><b>Fax:</b> 305-567-1317</div><div><b>Email:</b> info@alpha-1foundation.org</div><div>
<a href="http://www.alpha-1foundation.org" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">www.alpha-1foundation.org</a>
</div></li><li class="half_rhythm"><div>
<b>MedlinePlus</b>
</div><div>
<a href="https://medlineplus.gov/genetics/condition/alpha-1-antitrypsin-deficiency/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Alpha-1 antitrypsin deficiency</a>
</div></li><li class="half_rhythm"><div>
<b>NCBI Genes and Disease</b>
</div><div>
<a href="/books/NBK22199/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Alpha -1-antitrypsin deficiency</a>
</div></li><li class="half_rhythm"><div>
<b>American Liver Foundation</b>
</div><div><b>Phone:</b> 800-465-4837 (HelpLine)</div><div>
<a href="http://www.liverfoundation.org" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">liverfoundation.org</a>
</div></li><li class="half_rhythm"><div>
<b>Canadian Liver Foundation</b>
</div><div>Canada</div><div><b>Phone:</b> 800-563-5483</div><div><b>Email:</b> clf@liver.ca</div><div>
<a href="http://www.liver.ca" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">www.liver.ca</a>
</div></li><li class="half_rhythm"><div>
<b>Childhood Liver Disease Research Network (ChiLDReN)</b>
</div><div><b>Phone:</b> 720-777-2598</div><div><b>Email:</b> joan.hines@childrenscolorado.org</div><div>
<a href="https://childrennetwork.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">www.childrennetwork.org</a>
</div></li><li class="half_rhythm"><div>
<b>Children's Liver Disease Foundation</b>
</div><div>United Kingdom</div><div><b>Phone:</b> +44 (0) 121 212 3839</div><div><b>Email:</b> info@childliverdisease.org</div><div>
<a href="http://www.childliverdisease.org" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">childliverdisease.org</a>
</div></li><li class="half_rhythm"><div>
<b>National Organization for Rare Disorders (NORD)</b>
</div><div><b>Phone:</b> 800-999-6673</div><div>
<a href="https://rarediseases.org/for-patients-and-families/help-access-medications/patient-assistance-programs-2/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">RareCare&#x000ae; Patient Assistance Programs</a>
</div></li><li class="half_rhythm"><div>
<b>Alpha-1 Canadian Registry</b>
</div><div>Toronto Western Hospital</div><div>399 Bathurst Street</div><div>7th Floor, East Wing, Room 445</div><div>Toronto Ontario M5T 2S8</div><div>Canada</div><div><b>Phone:</b> 800-352-8186 (toll-free); 416-603-5020</div><div><b>Fax:</b> 416-603-5020</div><div><b>Email:</b> alpha1canadianregistry@gmail.com</div><div>
<a href="http://www.alpha1canadianregistry.com" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">www.alpha1canadianregistry.com</a>
</div></li><li class="half_rhythm"><div>
<b>Alpha-1 Research Registry</b>
</div><div><b>Phone:</b> 877-228-7321 ext 252</div><div><b>Email:</b> alpha1registry@alpha1.org</div><div>
<a href="https://www.alpha1.org/investigators/resources/research-registry/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">www.alpha1.org/investigators/resources/research-registry</a>
</div></li></ul>
</div><div id="alpha1-a.Molecular_Genetics"><h2 id="_alpha1-a_Molecular_Genetics_">Molecular Genetics</h2><p><i>Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. &#x02014;</i>ED.</p><div id="alpha1-a.molgen.TA" class="table"><h3><span class="label">Table A.</span></h3><div class="caption"><p>Alpha-1 Antitrypsin Deficiency: Genes and Databases</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.molgen.TA/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.molgen.TA_lrgtbl__"><table class="no_bottom_margin"><tbody><tr><th id="hd_b_alpha1-a.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">Gene</th><th id="hd_b_alpha1-a.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">Chromosome Locus</th><th id="hd_b_alpha1-a.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">Protein</th><th id="hd_b_alpha1-a.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">Locus-Specific Databases</th><th id="hd_b_alpha1-a.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">HGMD</th><th id="hd_b_alpha1-a.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">ClinVar</th></tr><tr><td headers="hd_b_alpha1-a.molgen.TA_1_1_1_1" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="/gene/5265" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=gene">
<i>SERPINA1</i>
</a>
</td><td headers="hd_b_alpha1-a.molgen.TA_1_1_1_2" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="https://www.ncbi.nlm.nih.gov/genome/gdv/?context=gene&#x00026;acc=5265" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">14q32<wbr style="display:inline-block"></wbr>​.13</a>
</td><td headers="hd_b_alpha1-a.molgen.TA_1_1_1_3" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="http://www.uniprot.org/uniprot/P01009" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">Alpha-1-antitrypsin</a>
</td><td headers="hd_b_alpha1-a.molgen.TA_1_1_1_4" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="https://research.cchmc.org/LOVD2/home.php?select_db=SERPINA1" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">CCHMC - Human Genetics Mutation Database (SERPINA1)</a>
</td><td headers="hd_b_alpha1-a.molgen.TA_1_1_1_5" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="http://www.hgmd.cf.ac.uk/ac/gene.php?gene=SERPINA1" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">SERPINA1</a>
</td><td headers="hd_b_alpha1-a.molgen.TA_1_1_1_6" rowspan="1" colspan="1" style="vertical-align:top;">
<a href="https://www.ncbi.nlm.nih.gov/clinvar/?term=SERPINA1[gene]" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">SERPINA1</a>
</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div id="alpha1-a.TFA.1"><p class="no_margin">Data are compiled from the following standard references: <a class="def" href="/books/n/gene/glossary/def-item/gene/">gene</a> from
<a href="http://www.genenames.org/index.html" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">HGNC</a>;
<a class="def" href="/books/n/gene/glossary/def-item/chromosome/">chromosome</a> <a class="def" href="/books/n/gene/glossary/def-item/locus/">locus</a> from
<a href="http://www.omim.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">OMIM</a>;
protein from <a href="http://www.uniprot.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">UniProt</a>.
For a description of databases (Locus Specific, HGMD, ClinVar) to which links are provided, click
<a href="/books/n/gene/app1/">here</a>.</p></div></dd></dl></div></div></div><div id="alpha1-a.molgen.TB" class="table"><h3><span class="label">Table B.</span></h3><div class="caption"><p>OMIM Entries for Alpha-1 Antitrypsin Deficiency (<a href="/omim/107400,613490" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">View All in OMIM</a>) </p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.molgen.TB/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.molgen.TB_lrgtbl__"><table><tbody><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<a href="/omim/107400" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">107400</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">SERPIN PEPTIDASE INHIBITOR, CLADE A, MEMBER 1; SERPINA1</td></tr><tr><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">
<a href="/omim/613490" ref="pagearea=body&amp;targetsite=entrez&amp;targetcat=term&amp;targettype=omim">613490</a></td><td rowspan="1" colspan="1" style="text-align:left;vertical-align:top;">ALPHA-1-ANTITRYPSIN DEFICIENCY; A1ATD</td></tr></tbody></table></div></div><div id="alpha1-a.Molecular_Pathogenesis"><h3>Molecular Pathogenesis</h3><p><i>SERPINA1</i> encodes alpha-1 antitrypsin (AAT), a glycoprotein member of the serum protease inhibitor (serpin) family. The molecule is composed of 418 amino acids; the first 24 are the signal peptide, while residues 25-418 encode the mature protein. AAT provides more than 90% of the protection against neutrophil elastase in the lower airways.</p><p><b>Mechanism of disease causation.</b> The AAT disease mechanism can be either loss of function or gain of function.</p><ul><li class="half_rhythm"><div><b>Lung disease.</b> Alpha-1 antitrypsin deficiency (AATD) results in reduced inhibition of neutrophil elastase in the lung (which is increased in smokers), resulting in excessive destruction of the elastin in the alveolar walls. Thus, lung disease is considered to result from a <b><a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a></b> mechanism.</div></li><li class="half_rhythm"><div><b>Liver disease.</b> Abnormal AAT alleles (e.g., Z, M <sub>malton</sub>, S <sub>iiyama</sub>) polymerize within hepatocytes [<a class="bk_pop" href="#alpha1-a.REF.carrell.2002.45">Carrell &#x00026; Lomas 2002</a>], precluding secretion. Accumulation of abnormal AAT protein is associated with liver disease through a <b><a class="def" href="/books/n/gene/glossary/def-item/gain-of-function/">gain-of-function</a></b> mechanism [<a class="bk_pop" href="#alpha1-a.REF.kopito.2000.e207">Kopito &#x00026; Ron 2000</a>, <a class="bk_pop" href="#alpha1-a.REF.perlmutter.2002.1579">Perlmutter 2002</a>].</div></li></ul><p>Protein variants, such as the PI*S variant, are more easily degraded. The PI*Z variant polymerizes within hepatocytes and alveolar macrophages where it was shown to be chemotactic for neutrophils. Thus, in addition to a <a class="def" href="/books/n/gene/glossary/def-item/loss-of-function/">loss-of-function</a> mechanism, lung destruction may be fueled by an inflammatory reaction related to the polymers of Z protein variants in the lung [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.1997.394">McElvaney et al 1997</a>].</p><p><b><i>SERPINA1</i>-specific laboratory technical considerations.</b> Targeted testing for PI*Z, PI*S, PI*I, and PI*F is frequently performed. Differentiating targeted versus sequencing methods on a clinical report is important since targeted analysis detects about 95% of disease alleles.</p><div id="alpha1-a.T.notable_serpina1_pathogenic_v" class="table"><h3><span class="label">Table 9. </span></h3><div class="caption"><p>Notable <i>SERPINA1</i> Pathogenic Variants</p></div><p class="large-table-link" style="display:none"><span class="right"><a href="/books/NBK1519/table/alpha1-a.T.notable_serpina1_pathogenic_v/?report=objectonly" target="object">View in own window</a></span></p><div class="large_tbl" id="__alpha1-a.T.notable_serpina1_pathogenic_v_lrgtbl__"><table class="no_bottom_margin"><thead><tr><th id="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_1" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Reference Sequences</th><th id="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">DNA Nucleotide Change</th><th id="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Predicted Protein Change (Alias&#x000a0;<sup>1</sup>)</th><th id="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" scope="col" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">Comment [Reference]</th></tr></thead><tbody><tr><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_1" rowspan="6" scope="row" colspan="1" style="text-align:left;vertical-align:middle;">
<a href="https://www.ncbi.nlm.nih.gov/nuccore/NM_000295.4" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">NM_000295<wbr style="display:inline-block"></wbr>​.4</a>
<br />
<a href="https://www.ncbi.nlm.nih.gov/protein/NP_000286.3" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">NP_000286<wbr style="display:inline-block"></wbr>​.3</a>
</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">c.1096G&#x0003e;A</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu366Lys<br />(Glu342Lys)</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PI*Z; 95% of AATD-related disease results from homozygosity of this <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> (i.e., PI*ZZ) [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.1997.394">McElvaney et al 1997</a>]; aggregates in the liver [<a class="bk_pop" href="#alpha1-a.REF.carrell.2002.45">Carrell &#x00026; Lomas 2002</a>].</td></tr><tr><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.863A&#x0003e;T</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Glu288Val<br />(Glu264Val)</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PI*S; common <a class="def" href="/books/n/gene/glossary/def-item/pathogenic-variant/">pathogenic variant</a> when in combination w/other variants (i.e., PI*SZ) [<a class="bk_pop" href="#alpha1-a.REF.mcelvaney.1997.394">McElvaney et al 1997</a>]</td></tr><tr><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.226_228del</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Phe76del<br />(Phe52del)</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PI*M<sub>malton</sub>; aggregates in the liver [<a class="bk_pop" href="#alpha1-a.REF.carrell.2002.45">Carrell &#x00026; Lomas 2002</a>]</td></tr><tr><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.230C&#x0003e;T</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Ser77Phe<br />(Ser53Phe)</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PI*S<sub>iiyama</sub>; aggregates in the liver [<a class="bk_pop" href="#alpha1-a.REF.carrell.2002.45">Carrell &#x00026; Lomas 2002</a>]</td></tr><tr><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.739C&#x0003e;T</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg247Cys<br />(Arg223Cys)</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PI*F; quantitatively normal but functionally impaired in binding neutrophil elastase; PI*FF is diagnosed by molecular methods rather than serum AAT level alone [<a class="bk_pop" href="#alpha1-a.REF.sinden.2014.132">Sinden et al 2014</a>].</td></tr><tr><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_2" colspan="1" scope="row" rowspan="1" style="text-align:left;vertical-align:middle;">c.187C&#x0003e;T</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_3" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">p.Arg63Cys<br />(Arg39Cys)</td><td headers="hd_h_alpha1-a.T.notable_serpina1_pathogenic_v_1_1_1_4" rowspan="1" colspan="1" style="text-align:left;vertical-align:middle;">PI*I; common <a class="def" href="/books/n/gene/glossary/def-item/allele/">allele</a> assoc w/mild disease [<a class="bk_pop" href="#alpha1-a.REF.graham.1989.55">Graham et al 1989</a>]</td></tr></tbody></table></div><div><div><dl class="temp-labeled-list small"><dt></dt><dd><div><p class="no_margin">AAT = alpha-1 antitrypsin; AATD = alpha-1 antitrypsin deficiency</p></div></dd><dt></dt><dd><div><p class="no_margin">Variants listed in the table have been provided by the authors. <i>GeneReviews</i> staff have not independently verified the classification of variants.</p></div></dd><dt></dt><dd><div><p class="no_margin"><i>GeneReviews</i> follows the standard naming conventions of the Human Genome Variation Society (<a href="https://varnomen.hgvs.org/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">varnomen<wbr style="display:inline-block"></wbr>​.hgvs.org</a>). See <a href="/books/n/gene/app3/">Quick Reference</a> for an explanation of nomenclature.</p></div></dd><dt>1. </dt><dd><div id="alpha1-a.TF.9.1"><p class="no_margin">Variant designation that does not conform to current naming conventions; historical nomenclature does not include the signal sequence of the reference protein <a href="https://www.ncbi.nlm.nih.gov/protein/NP_000286.3" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">NP_000286<wbr style="display:inline-block"></wbr>​.3</a>, thereby decreasing the amino acid codon number by 24 amino acids for each variant.</p></div></dd></dl></div></div></div></div></div><div id="alpha1-a.Chapter_Notes"><h2 id="_alpha1-a_Chapter_Notes_">Chapter Notes</h2><div id="alpha1-a.Author_Notes"><h3>Author Notes</h3><p>Research Support, Non-US Government</p><p>Research Support, US Government, PHS</p></div><div id="alpha1-a.Author_History"><h3>Author History</h3><p>Loutfi S Aboussouan, MD (2014-present)<br />Diane W Cox, PhD, FCCMG, FRSC; University of Alberta (2005-2014)<br />Felicitas L Lacbawan, MD; Cleveland Clinic (2014-2020)<br />Kamilla Schlade-Bartusiak, PhD; University of Alberta (2005-2014)<br />James K Stoller, MD, MS (2014-present)<br />Vera Hupertz, MD (2020-present)</p></div><div id="alpha1-a.Revision_History"><h3>Revision History</h3><ul><li class="half_rhythm"><div>1 June 2023 (aa) Revision: <a href="/books/NBK1519/table/alpha1-a.T.relationship_of_aat_protein_v/?report=objectonly" target="object" rid-ob="figobalpha1aTrelationshipofaatproteinv">Table 4</a>: emphysema risk clarified to be lifetime emphysema risk</div></li><li class="half_rhythm"><div>21 May 2020 (ha) Comprehensive update posted live</div></li><li class="half_rhythm"><div>19 January 2017 (jks) Revision: clarification re serum levels of AAT in heterozygotes</div></li><li class="half_rhythm"><div>1 May 2014 (me) Comprehensive update posted live</div></li><li class="half_rhythm"><div>6 February 2008 (cd) Revision: <a class="def" href="/books/n/gene/glossary/def-item/sequence-analysis/">sequence analysis</a> available on a clinical basis</div></li><li class="half_rhythm"><div>27 October 2006 (me) Review posted live</div></li><li class="half_rhythm"><div>15 February 2005 (dc) Original submission</div></li></ul></div></div><div id="alpha1-a.References"><h2 id="_alpha1-a_References_">References</h2><div id="alpha1-a.Published_Guidelines__Consensus"><h3>Published Guidelines&#x000a0;/ Consensus Statements</h3><ul class="simple-list"><li class="half_rhythm"><div>American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Available <a href="https://www.atsjournals.org/doi/full/10.1164/rccm.168.7.818" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">online</a>. 2003. Accessed 5-23-23.</div></li><li class="half_rhythm"><div>Marciniuk DD, Hernandez P, Balter M, Bourbeau J, Chapman KR, Ford GT, Lauzon JL, Maltais F, O'Donnell DE, Goodridge D, Strange C, Cave AJ, Curren K, Muthuri S, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Available <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3373286/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">online</a>. 2012. Accessed 5-23-23.</div></li><li class="half_rhythm"><div>Sandhaus RA, Turino G, Brantly M, Campos M, Cross C, Goodman K, Hogarth K, Knight S, Stocks J, Stoller JK, Strange C, Teckman J. The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Available <a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5556762/" ref="pagearea=body&amp;targetsite=external&amp;targetcat=link&amp;targettype=uri">online</a>. 2016. Accessed 5-23-23.</div></li></ul></div><div id="alpha1-a.Literature_Cited"><h3>Literature Cited</h3><ul class="simple-list"><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.al_ashry.2017.170068">Al Ashry HS, Strange C. COPD in individuals with the PiMZ alpha-1 antitrypsin genotype. <span><span class="ref-journal">Eur Respir Rev. </span>2017;<span class="ref-vol">26</span>:170068. </span> [<a href="/pmc/articles/PMC9488576/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC9488576</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/29070580" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 29070580</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.alpha1_antitrypsin_deficiency_registry_study_group.1998.49">Alpha-1 Antitrypsin Deficiency Registry Study Group. Survival and FEV1 decline in individuals with severe deficiency of alpha-1 antitrypsin (Alpha-1 Antitrypsin Deficiency Registry Study Group). <span><span class="ref-journal">Am J Respir Crit Care Med. </span>1998;<span class="ref-vol">158</span>:49–59.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9655706" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 9655706</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.american_thoracic_society_european_respiratory_society.2003.818">American Thoracic Society, European Respiratory Society. American Thoracic Society / European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. <span><span class="ref-journal">Am J Respir Crit Care Med. </span>2003;<span class="ref-vol">168</span>:818–900.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/14522813" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 14522813</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.attaway.2019.2089">Attaway A, Majumdar U, Nowacki A, Sandhaus R, Stoller JK. An analysis of the degree of concordance among international guidelines regarding alpha-1 antitrypsin deficiency. <span><span class="ref-journal">Int J Chron Obstruct Pulmon Dis. </span>2019;<span class="ref-vol">14</span>:2089–101.</span> [<a href="/pmc/articles/PMC6734458/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC6734458</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31564856" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 31564856</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.bornhorst.2013.1000">Bornhorst JA, Greene DN, Ashwood ER, Grenache DG. &#x003b1;1-Antitrypsin phenotypes and associated serum protein concentrations in a large clinical population. <span><span class="ref-journal">Chest. </span>2013;<span class="ref-vol">143</span>:1000–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/23632999" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 23632999</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.boss_.2019.427">Boss&#x000e9; Y, Lamontagne M, Gaudreault N, Racine C, Levesque MH, Smith BM, Auger D, Clemenceau A, Par&#x000e9; M&#x000c8;, Laviolette L, Tremblay V, Maranda B, Morissette MC, Maltais F. Early-onset emphysema in a large French-Canadian family: a genetic investigation. <span><span class="ref-journal">Lancet Respir Med. </span>2019;<span class="ref-vol">7</span>:427–36.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/31000475" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 31000475</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.brantly.1991.703">Brantly ML, Wittes JT, Vogelmeier CF, Hubbard RC, Fells GA, Crystal RG. Use of a highly purified alpha-1 antitrypsin standard to establish ranges for the common normal and deficient alpha-1 antitrypsin phenotypes. <span><span class="ref-journal">Chest. </span>1991;<span class="ref-vol">100</span>:703–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1889260" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 1889260</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.campbell.2000">Campbell EJ. Alpha-1 antitrypsin deficiency: incidence and detection program. Respir Med. 2000;94 Suppl C:18-21. [<a href="https://pubmed.ncbi.nlm.nih.gov/10954251" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 10954251</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.carrell.2002.45">Carrell RW, Lomas DA. Alpha-1 antitrypsin deficiency - a model for conformational diseases. <span><span class="ref-journal">N Engl J Med. </span>2002;<span class="ref-vol">346</span>:45–53.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/11778003" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 11778003</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.corda.2008.61">Corda L, Bertella E, La Piana GE, Boni E, Redolfi S, Tantucci C. Inhaled corticosteroids as additional treatment in alpha-1-antitrypsin-deficiency-related COPD. <span><span class="ref-journal">Respiration. </span>2008;<span class="ref-vol">76</span>:61–8.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18319586" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 18319586</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.cox.2004.468">Cox DW. Prenatal diagnosis for alpha-1 antitrypsin deficiency. <span><span class="ref-journal">Prenat Diagn. </span>2004;<span class="ref-vol">24</span>:468–70.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15229848" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 15229848</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.cox.1980.429">Cox DW, Johnson AM, Fagerhol M. Report of nomenclature meeting for alpha-1 antitrypsin. <span><span class="ref-journal">Hum Genet. </span>1980;<span class="ref-vol">53</span>:429–33.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/6102963" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 6102963</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.cox.1983.221">Cox DW, Smyth S. 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The diagnosis and management of alpha-1 antitrypsin deficiency in the adult. <span><span class="ref-journal">Chronic Obstr Pulm Dis. </span>2016;<span class="ref-vol">3</span>:668–82.</span> [<a href="/pmc/articles/PMC5556762/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC5556762</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/28848891" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 28848891</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.seersholm.1997.2260">Seersholm N, Wencker M, Banik N, Viskum K, Dirksen A, Kok-Jensen A, Konietzko N. Does alpha-1 antitrypsin augmentation therapy slow the annual decline in FEV1 in patients with severe hereditary alpha-1 antitrypsin deficiency? Wissenschaftliche Arbeitsgemeinschaft zur Therapie von Lungenerkrankungen (WATL) Alpha-1 AT study group. <span><span class="ref-journal">Eur Respir J. </span>1997;<span class="ref-vol">10</span>:2260–3.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/9387950" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 9387950</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.smith.2014.94.e7">Smith BM, Austin JH, Newell JD Jr, D'Souza BM, Rozenshtein A, Hoffman EA, Ahmed F, Barr RG. Pulmonary emphysema subtypes on computed tomography: the MESA COPD study. <span><span class="ref-journal">Am J Med. </span>2014;<span class="ref-vol">127</span>:94.e7–23.</span> [<a href="/pmc/articles/PMC3882898/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC3882898</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/24384106" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 24384106</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.sinden.2014.132">Sinden NJ, Koura F, Stockley RA. The significance of the F variant of alpha-1 antitrypsin and unique case report of a PiFF homozygote. <span><span class="ref-journal">BMC Pulm Med. </span>2014;<span class="ref-vol">14</span>:132–9.</span> [<a href="/pmc/articles/PMC4131482/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC4131482</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/25098359" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 25098359</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.s_rheim.2010.1125">S&#x000f8;rheim IC, Bakke P, Gulsvik A, Pillai SG, Johannessen A, Gaarder PI, Campbell EJ, Agust&#x000ed; A, Calverley PM, Donner CF, Make BJ, Rennard SI, Vestbo J, Wouters EF, Par&#x000e9; PD, Levy RD, Coxson HO, Lomas DA, Hersh CP, Silverman EK. &#x003b1;<sub>1</sub>-antitrypsin protease inhibitor MZ heterozygosity is associated with airflow obstruction in two large cohorts. <span><span class="ref-journal">Chest. </span>2010;<span class="ref-vol">138</span>:1125–32.</span> [<a href="/pmc/articles/PMC2972629/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC2972629</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/20595457" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 20595457</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.spratt.2019.1130">Spratt JR, Brown RZ, Rudser K, Goswami U, Hertz MI, Patil J, Cich I, Shumway SJ, Loor G. Greater survival despite increased complication rates following lung transplant for alpha-1-antitrypsin deficiency compared to chronic obstructive pulmonary disease. <span><span class="ref-journal">J Thorac Dis. </span>2019;<span class="ref-vol">11</span>:1130–44.</span> [<a href="/pmc/articles/PMC6531741/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC6531741</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/31179055" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 31179055</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.stoller.2005.2225">Stoller JK, Aboussouan LS. Alpha-1 antitrypsin deficiency. <span><span class="ref-journal">Lancet. </span>2005;<span class="ref-vol">365</span>:2225–36.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/15978931" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 15978931</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.stoller.2008.113">Stoller JK, Piliang M. Panniculitis in alpha-1 antitrypsin deficiency: a review. <span><span class="ref-journal">Clin Pulm Med. </span>2008;<span class="ref-vol">15</span>:113–7.</span></div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.strnad.2020.1443">Strnad P, McElvaney NG, Lomas DA. Alpha-1 antitrypsin deficiency. <span><span class="ref-journal">New Engl J Med. </span>2020;<span class="ref-vol">382</span>:1443–55.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/32268028" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 32268028</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.sveger.1976.1316">Sveger T. Liver disease in alpha-1 antitrypsin deficiency detected by screening of 200,000 infants. <span><span class="ref-journal">N Engl J Med. </span>1976;<span class="ref-vol">294</span>:1316–21.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/1083485" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 1083485</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.sveger.1988.847">Sveger T. The natural history of liver disease in alpha-1 antitrypsin deficient children. <span><span class="ref-journal">Acta Paediatr Scand. </span>1988;<span class="ref-vol">77</span>:847–51.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/2905108" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 2905108</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.takahashi.1990.403">Takahashi H, Crystal RG. Alpha 1-antitrypsin Null(isola di procida): an alpha 1-antitrypsin deficiency allele caused by deletion of all alpha 1-antitrypsin coding exons. <span><span class="ref-journal">Am J Hum Genet. </span>1990;<span class="ref-vol">47</span>:403–13.</span> [<a href="/pmc/articles/PMC1683852/" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pmc">PMC free article<span class="bk_prnt">: PMC1683852</span></a>] [<a href="https://pubmed.ncbi.nlm.nih.gov/1975477" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 1975477</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.tanash.2008.1091">Tanash HA, Nilsson PM, Nilsson JA, Piitulainen E. Clinical course and prognosis of never-smokers with severe alpha-1 antitrypsin deficiency (PiZZ). <span><span class="ref-journal">Thorax. </span>2008;<span class="ref-vol">63</span>:1091–5.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/18682522" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 18682522</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.tejwani.2019.915">Tejwani V, Nowacki A, Fye E, Sanders C, Stoller JK. The impact of delayed diagnosis of alpha-1 antitrypsin deficiency: the association between diagnostic delay and worsened clinical status. <span><span class="ref-journal">Respir Care. </span>2019;<span class="ref-vol">64</span>:915–22.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/30914495" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 30914495</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.volpert.2000.258">Volpert D, Molleston JP, Perlmutter DH. Alpha-1 antitrypsin deficiency-associated liver disease progresses slowly in some children. <span><span class="ref-journal">J Pediatr Gastroenterol Nutr. </span>2000;<span class="ref-vol">31</span>:258–63.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/10997369" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 10997369</span></a>]</div></li><li class="half_rhythm"><div class="bk_ref" id="alpha1-a.REF.wencker.2002.319">Wencker M, Marx A, Konietzko N, Schaefer B, Campbell EJ. Screening for alpha-1 Pi deficiency in patients with lung diseases. <span><span class="ref-journal">Eur Respir J. </span>2002;<span class="ref-vol">20</span>:319–24.</span> [<a href="https://pubmed.ncbi.nlm.nih.gov/12212962" ref="pagearea=cite-ref&amp;targetsite=entrez&amp;targetcat=link&amp;targettype=pubmed">PubMed<span class="bk_prnt">: 12212962</span></a>]</div></li></ul></div></div><div id="bk_toc_contnr"></div></div></div>
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class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper two_line"><a class="brieflinkpopperctrl" href="/pubmed/20301668" ref="ordinalpos=1&amp;linkpos=2&amp;log$=relatedreviews&amp;logdbfrom=pubmed"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.</a><span class="source">[GeneReviews(®). 1993]</span><div class="brieflinkpop offscreen_noflow"><span xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="invert">Review</span> Hemophilia B.<div class="brieflinkpopdesc"><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="author">Konkle BA, Nakaya Fletcher S. </em><em xmlns:np="http://ncbi.gov/portal/XSLT/namespace" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" class="cit">GeneReviews(®). 1993</em></div></div></li><li class="brieflinkpopper 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