Alpha-1 antitrypsin deficiency (AATD) was the first genetic risk factor for chronic obstructive pulmonary disease (COPD) described. In the more than 50 years since its description, the disease continues to provide insights into more common forms of COPD. Although AATD is caused by a single genetic variant, the clinical manifestations of disease include panacinar emphysema, airway hyperresponsiveness, and bronchiectasis. With improved molecular understanding of the mechanisms of disease pathogenesis and progression, new therapies in addition to intravenous augmentation therapy are on the horizon.
Key points
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Alpha-1 antitrypsin deficiency (AATD) diagnosis requires a test from all individuals with chronic obstructive pulmonary disease (COPD). Attempts to clinically characterize this genetic condition to decide who needs testing miss affected individuals.
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Airway disease in AATD can take the form of asthma, chronic bronchitis, or bronchiectasis.
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Augmentation therapy with plasma-derived alpha-1 protease inhibitor slows the progression of emphysema in randomized trials and is associated with strong signals of improved mortality in observational cohorts.
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Clinical liver disease occurs in approximately 10% of patients with AATD. Tests for cirrhosis should occur at least yearly in PiZZ individuals to recognize this complication.
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A diagnosis of AATD-associated COPD establishes a family at risk. Family testing for AATD is the most cost-effective and successful strategy to find patients who may benefit from lifestyle interventions or therapies.
Introduction
Alpha-1 antitrypsin (AAT) is the most abundant serine proteinase inhibitor in human plasma. When Laurell and Erikson first noted the association between a deficiency of the protein (AAT deficiency [AATD]) and emphysema in 1963, they were likely unaware that interest in the mechanisms of chronic obstructive pulmonary disease (COPD) pathogenesis associated with AATD would continue for the next half century. Genetically determined deficiency of AAT is associated with emphysema, particularly in individuals who smoke cigarettes or are exposed to other inhaled particulates and/or fumes. , Features of this unique endotype of COPD continue to inform aspects of smoking-related COPD and suggest the pathway forward if cigarette cessation is ever eliminated as a public health risk. In AATD, COPD continues to progress with aging in the absence of smoking. As such, this disease helps answer questions on genetic risks, protease/antiprotease biology, and translation of these findings to the AATD patients in the clinic.
Alpha-1 Antitrypsin Synthesis and Regulation
AAT is a 52-kDa glycoprotein produced mainly in hepatocytes , but also synthesized by blood monocytes, macrophages, pulmonary alveolar cells, and other cells throughout the body. Daily hepatic production of AAT of more than 30 mg/kg body weight results in high plasma concentrations, ranging from 90 mg/dL to 175 mg/dL that further increase during times of stress. Because of an acute-phase response, particularly after interleukin (IL)-6, IL-1, tumor necrosis factor α, or endotoxin, , AAT levels are higher during times of infections and tissue inflammation, accounting for high concentrations in patients with normal genotypes in intensive care units. The tissue concentration of the protein is reduced to approximately 10% of the plasma levels in the fluid of the lower respiratory tract. , AAT also diffuses through endothelial and epithelial cell walls. AAT expression also is autoregulated with enhanced synthesis after exposure to neutrophil elastase (NE) either alone or complexed to AAT.
Alpha-1 Antitrypsin Structure and Mechanisms of Protease Inhibitory Activity
Human AAT has a single polypeptide chain of 394 amino acid residues and 3 carbohydrate side chains. The reactive site loop is susceptible to protease attack in which the reactive site loop migrates to form a stable complex between the inhibitor and the proteinase. , The inhibitory activity of AAT is strong for NE, proteinase 3, and other serine proteases. In addition, AAT also inhibits some cysteine proteinases, including caspase-3. , Complexes of AAT and the affected proteases can be measured in the lower airway, and signatures of cleavage products further inform the protease-antiprotease balance in the lung. , AAT, like other serpins, can be inactivated by oxidants and proteases that are not inhibitor targets. This occurs clinically in cigarette smoking, in which the AAT molecule can be cleaved by oxidant injury in the local environment of the lung. The genesis of the protease-antiprotease balance model of emphysema pathogenesis was initiated with the discovery of AATD but may play large roles in other forms of AAT replete COPD.
Genetic Modifications of the Alpha-1 Antitrypsin Molecule
The usual serum AAT concentrations are determined by the genetic alleles depicted in Fig. 1 . Because of the variability of serum AAT concentrations every day due to stress, associations with human disease are best correlated with AAT gene mutations. The AAT molecule is produced on the SERPINA1 gene (OMIM: 107400 ), and approximately 130 pathogenic variations in human gene structure have been defined. AAT nomenclature is unique, because the clinical disease states originally were defined by plasma protein determination rather than by sequencing. The protease inhibitor (Pi) system informs the AAT concentration as product of each of 2 alleles in a codominant fashion. For example, the variant PiMZ has 1 M allele (a normally functioning allele) and 1 Z mutation that produces low serum AAT levels. The resulting serum level is intermediate between normal and severely deficient. Unlike most clinical diseases, the AATD deficiency states were called phenotypes. Recently, polymerase chain reaction (PCR) and gene sequencing have been used to probe blood DNA to define these phenotypes by specific gene presence. There are a few rare genetic variants that produce dysfunctional AAT proteins. PiF and PiI produce near-normal AAT concentrations, but the association constant with elastase is markedly reduced. Table 1 lists some common allelic variants of SERPINA1. Recently, buccal swab samples that test for 14 deficiency alleles are available.
| Exon | Comments | ||
|---|---|---|---|
| Normal alleles | M1 (Ala213) | III | Most common M allele |
| M1 (Val213) | III | ||
| M2 | II | ||
| M3 | V | ||
| M4 | II | ||
| M5 | II | 2 alleles, M5 berlin and M5 karlsruhe | |
| M6 | II | ||
| L | II, III, V | 2 alleles, L frankfurt and L offenbach | |
| V | II, V | 3 alleles, V, V donauworth , and V munich | |
| X | III, V | 2 alleles, X and X christchurch | |
| B | Unknown | B alhambra | |
| P | III, V | 2 alleles, P st. louis and P albans | |
| Deficiency alleles | Z | V | Most common severe deficiency gene |
| S | III | Lesser degrees of deficiency than Z gene but more common | |
| M alleles | II, V | M herleen , M malton , M mineral springs , M procida , M bethesda , M palermo , and M nichinan | |
| W | V | ||
| I | II | Near-normal serum level with dysfunctional protein | |
| P | III | 2 alleles, P lowell and P duarte | |
| Dysfunctional allele | F | III | Low-normal serum level with dysfunctional protein |
| Pittsburg | V | ||
PiZ and PiS are the most common severe deficiency alleles. Recent evidence suggests that carriers of 1 S allele (PiMS) are functionally normal. In contrast, carriers of 1 Z allele (PiMZ) that make up 2% to 3% of the US population have a higher risk of COPD if they smoke compared with PiMM normals. In addition, studies evaluating genes associated with progression of COPD have shown the PiMZ state to be independently correlated with disease progression. Similar findings in smoking versus nonsmoking PiSZ individuals recently have been described.
The Z variant produces a misfolded protein that cannot get out of the hepatic endoplasmic reticulum and causes polymers. In the homozygous condition (PiZZ), serum concentrations of AAT are approximately 10% to 15% of normal, and AAT accumulates in hepatocytes where it can cause cirrhosis. A variety of SERPINA1 gene variants (cumulatively called the null alleles) produce no appreciable AAT at the cellular level and, therefore, have no excess risk for clinical liver disease. Gene distribution studies have found PiZ alleles in almost every country of the world, although of lower frequency in Asian and African populations.
The epidemiology of AATD suggests that between 47,000 and 100,000 PiZZ-affected individuals live in the United States. At most, 10,000 to 15,000 individuals have been identified. The most commonly cited reason for the low diagnosis rate is failure to follow published guidelines that have been in place since 2003 to test every individual with COPD once in a lifetime ( Box 1 ). As a result of not testing, the diagnostic delay from onset of COPD diagnosis to a diagnosis of AATD approximates 7 years and was not getting better when last evaluated.
