Alpha-1-antitrypsin (AAT) is the chief protease inhibitor (PI) in human serum. Alterations in the production of this PI may result in the degradation of the connective protein elastin in lung alveoli, which increases the risk for developing lung disease. Additionally, severe AAT deficiency may cause improper folding of the AAT protein leading to deposition in hepatocytes and corresponding liver disease.
Chronic obstructive pulmonary disease (COPD) caused by AAT deficiency (AATD-COPD) is the fourth most common factor associated with lung transplantation. Pooled plasma AAT infusions can be used to treat lung disease in patients with AATD-COPD; however, this treatment does not address liver disease caused by AAT deficiency (Sandhaus, 2016).
Diagnosis
Indications for Testing
- Chronic obstructive pulmonary disease (COPD) or unexplained bronchiectasis, regardless of age or ethnicity
- Unexplained chronic liver disease
- Necrotizing panniculitis or granulomatosis with polyangiitis
- First-degree relative with 1 or 2 pathogenic alpha-1-antitrypsin (AAT) gene variants
- Family history of AAT deficiency
- Newborns with bleeding disorder or prolonged jaundice
Laboratory Testing
- Diagnostic testing for symptomatic individuals
Protease Inhibitor (PI) Typing (Phenotyping) | Genotyping of S and Z Alleles | AAT Serum Concentration | AAT Gene Sequencing (Expanded Genotyping) | |
---|---|---|---|---|
Rationale |
Detect abnormal phenotypes |
Identify causative S and Z DNA variants |
Evaluate AAT protein concentration
|
Identify rare pathogenic variants |
Strengths |
Considered gold standard; identifies all abnormally migrating proteins |
Identify 95% of affected individuals Allow for prenatal diagnosis in at-risk pregnancies |
Determine AAT enzyme plasma concentration for the initial evaluation of AAT deficiency |
Identify variants other than S and Z alleles |
Limitations |
May not be able to accurately identify rare deficiency alleles Does not detect null alleles |
Does not detect rare deficiency alleles including null alleles |
Serum AAT concentration has low sensitivity for AAT deficiency because AAT is an acute phase reactant and may be elevated by other disease processes |
|
Description |
Isoelectric focusing |
Molecular testing of SERPINA1 gene |
Quantification of AAT protein in serum |
Molecular sequencing of SERPINA1 |
- Testing of asymptomatic high-risk individuals
- First-degree relatives of affected individuals
- Molecular testing of known familial variant
Imaging Studies
- Computed tomography (CT) scan of chest
- Recommended in newly diagnosed patients who are symptomatic or have abnormal pulmonary function testing results (Sandhaus, 2016)
Differential Diagnosis
- Adults
- Non-AAT COPD
- Cystic fibrosis
- Cirrhosis from other etiologies
- Pediatric
- Viral infection
- Hemochromatosis
- Wilson disease
- Autoimmune hepatitis
- Inborn errors of metabolism
Screening
- American Thoracic Society (ATS) and European Respiratory Society (ERS) Guidelines (2003)
- Neonatal screening: not recommended despite high prevalence of deficiency in population
- Screening in individuals >11 years: may be indicated in areas of high alpha-1-antitrypsin (AAT) deficiency prevalence or in areas of high smoking rates
Monitoring
- Pulmonary disease (Sandhaus, 2016)
- Measure lung function with baseline spirometry and annual spirometry follow-up
- Computed tomography (CT) of chest not recommended for monitoring
- Liver disease: monitor annually unless clinically indicated sooner (Sandhaus, 2016)
- Laboratory monitoring
- Aspartate aminotransferase (AST)
- Alanine aminotransferase (ALT)
- Gamma-glutamyl transferase (GGT)
- Albumin, bilirubin
- International normalized ratio (INR)
- Platelets
- Physical examination of abdomen
- Liver ultrasound
- Laboratory monitoring
Background
Epidemiology
- Prevalence
- AAT deficiency affects ~2-3% of the 2-3 million patients with COPD in U.S.
- Severe deficiency: 1/6,000 in White populations; less frequent in other ethnicities
- Incidence of variants: 1/3,000-5,000 individuals of European ancestry
- Age
- Smokers develop lung disease in 40s
- Nonsmokers develop lung disease in 50s
Risk Factors
- Tobacco use
- Increases risk of developing severe lung disease; symptoms begin ≥10 years earlier than in nonsmokers
- Oxidants in tobacco smoke inactivate AAT protein, causing further AAT impairment
- Occupational dust/fumes
- Liver insults
Genetics
- SERPINA1
- Gene located on chromosome 14q31-q32.3
- Inheritance: codominant
- >100 variants identified: most are benign
- Pathogenic variant (c.1024G>A; p.E324K), known as Z allele by phenotyping, is most common severe deficiency variant
- Pathogenic variant (c.791A>T; p.E264V), known as S allele by phenotyping, is most common moderate deficiency variant
- 95% of White individuals have the M allele by phenotyping (ie, no variants present in the AAT gene [wild type])
Allele Variants | AAT Activity | Emphysema Risk | Liver Disease Risk |
---|---|---|---|
MM |
100% |
Background |
Low |
MS |
80% |
Background |
Low |
MZ |
58% |
Background |
Low |
SS |
60% |
Background |
Low |
SZ |
20-50% |
Intermediate |
|
ZZ |
15% |
80-100% |
Moderately high – high |
Null-Null |
0% |
100% |
Background |
Pathophysiology
- AAT is a glycoprotein mainly synthesized by the liver
- AAT deficiency results in uninhibited free neutrophil elastase, which leads to degradation of connective protein elastin in alveoli
- Hepatic disease is secondary to accumulation of improperly folded, unsecreted AAT in hepatocytes
Clinical Presentation
- Adults
- Pulmonary: dyspnea, wheezing, cough, phlegm, and early onset emphysema (panacinar)
- Hepatic: liver dysfunction, cirrhosis
- Occurs more often in individuals with Z allele
- Hepatitis with jaundice
- Chronic liver disease
- Skin: panniculitis
- Necrotic areas with spontaneous suppuration
- Neonates
- Small percentage of affected newborns have hepatitis with cholestatic jaundice (prolonged jaundice with conjugated hyperbilirubinemia)
- Low AAT levels are also found in neonatal respiratory distress syndrome and severe protein-losing disorders
- Rare associated diseases
- Granulomatosis with polyangiitis, necrotizing panniculitis, and aneurysms of aortic and brain arteries
- Complications
- Hepatocellular carcinoma and cholangiocarcinoma
ARUP Laboratory Tests
Preferred test to identify alpha-1-antitrypsin (AAT) deficiency and causative DNA and protein variants
Only Z (c.1024G>A, p.E342K) and S (c.791A>T, p.E264V) alleles are detected by genotyping
Acutely ill AAT-deficient patients may have falsely normal AAT concentrations
Diagnostic errors may occur due to rare probe-site mutations
Immunoturbidimetry/Polymerase Chain Reaction/Fluorescence Monitoring/Isoelectric Focusing
Determine specific AAT protein variant(s) in individual with decreased concentration of AAT (<90mg/dL)
Acutely ill AAT-deficient patients may have falsely normal AAT concentrations
Qualitative Isoelectric Focusing/Immunoturbidimetry
Determine AAT enzyme plasma concentration for the initial evaluation of AAT deficiency
Acutely ill AAT-deficient patients may have falsely normal AAT concentrations
Quantitative Immunoturbidimetry
Aid in histologic diagnosis of AAT
Stained and returned to client pathologist; if consultation required, contact anatomic pathology, surgical consult, or hematopathology
Immunohistochemistry
References
14522813
American Thoracic Society. American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med. 2003;168(7):818-900.
NIH - Alpha-1 antitrypsin deficiency
National Institutes of Health, U.S. National Library of Medicine. Genetics Home Reference: Alpha-1 antitrypsin deficiency. [Reviewed: Jan 2013; Accessed: Jun 2017]
20955965
Bals R. Alpha-1-antitrypsin deficiency. Best Pract Res Clin Gastroenterol. 2010;24(5):629-633.
22426792
Ferrarotti I, Thun GA, Zorzetto M, et al. Serum levels and genotype distribution of α1-antitrypsin in the general population. Thorax. 2012;67(8):669-674.
18565211
Fregonese L, Stolk J. Hereditary alpha-1-antitrypsin deficiency and its clinical consequences. Orphanet J Rare Dis. 2008;3:16.
GOLD - Global Strategy for Diagnosis, Management, and Prevention of COPD
Global strategy for diagnosis, management, and prevention of COPD. Global Initiative for Chronic Obstructive Lung Disease. [Accessed: Jun 2017]
18187064
Köhnlein T, Welte T. Alpha-1 antitrypsin deficiency: pathogenesis, clinical presentation, diagnosis, and treatment. Am J Med. 2008;121(1):3-9.
22536580
Marciniuk DD, Hernandez P, Balter M, et al. Alpha-1 antitrypsin deficiency targeted testing and augmentation therapy: a Canadian Thoracic Society clinical practice guideline. Can Respir J. 2012;19(2):109-116.
25726555
McElvaney NG. Diagnosing α1-antitrypsin deficiency: how to improve the current algorithm. Eur Respir Rev. 2015;24(135):52-57.
21960536
Stoller JK, Aboussouan LS. A review of α1-antitrypsin deficiency. Am J Respir Crit Care Med. 2012;185(3):246-259.
28848891
Sandhaus RA, Turino G, Brantly ML, et al. Clinical guidelines for the diagnosis and management of alpha-1 antitrypsin deficiency in the adult. Chronic Obstr Pulm Dis. 2016;3(3):668-682.
Medical Experts
Genzen

LaGrave

Mao
